Skip to main content
SpringerLink
Log in

Mechanistic and Pharmacological Insights into Modulation of ABC Drug Transporters by Tyrosine Kinase Inhibitors

  • Chapter
  • First Online:
ABC Transporters - 40 Years on

  • 1102 Accesses

Abstract

ATP-binding cassette (ABC) drug transporters have both physiological and pharmacological importance in humans. They not only protect the cells from xenobiotics, but also alter the pharmacokinetics and toxicity of drugs that are substrates for these transporters. P-glycoprotein (P-gp) was the first human ABC transporter to be discovered, almost four decades ago. Drug transport using the energy harvested by ATP hydrolysis is a hallmark of ABC drug transporters and has been extensively studied to determine its mechanism of substrate specificity and transport activity. Structural information from a number of human P-gp homologs highlights the existence of multiple drug-binding sites that can interact with a diverse set of chemically or structurally unrelated compounds. Tyrosine kinase inhibitors (TKIs) comprise a class of drugs that interact with ABC transporters with high affinity and are reported to be transport substrates of several ABC transporters. A number of preclinical and clinical studies have shown that ABC transporters influence the disposition of several TKIs that include altered pharmacokinetics and safety profiles and have a role in the development of resistance to this class of therapeutics. Structural details regarding the TKIs’ effect on ABC transporters have not been thoroughly explored. This review summarizes preclinical and clinical observations on the interaction of TKIs with ABC drug transporters. In addition, we provide structural information on the interaction of two TKIs, nilotinib and imatinib, at the drug-binding regions within P-gp and ABCG2. This information could help to generate a novel scaffold that would be an ideal TKI with potent inhibition of kinases, but minimal interactions with ABC drug transporters.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ABCB1:

ATP-binding cassette subfamily B member 1

ABCG2:

ATP-binding cassette subfamily G member 2

ALK:

Anaplastic lymphoma kinase

AML:

Acute myeloid leukemia

BCR-ABL:

Breakpoint cluster-Abelson

BCRP:

Breast cancer resistance protein

CML:

Chronic myeloid leukemia

EGFR:

Epidermal growth factor receptor

FAK:

Focal adhesion kinase

FGFR:

Fibroblast growth factor receptor

GIST:

Gastrointestinal stromal tumor

HER2:

Human epidermal growth factor receptor 2

IAAP:

Iodoarylazidoprazosin

JAK:

Janus kinase

MAPK:

Mitogen-activated protein kinase

MDR:

Multidrug resistance

MRP1:

Multidrug resistance-associated protein 1

MRP7:

Multidrug resistance-associated protein 7

NSCLC:

Non-small-cell lung adenocarcinoma

P-gp:

P-glycoprotein

PDGFR:

Platelet-derived growth factor receptor

RTK:

Receptor tyrosine kinase

TMD:

Transmembrane domain

TKIs:

Tyrosine kinase inhibitors

VEGFR:

Vascular endothelial growth factor receptor

References

  • Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB (2006) Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24(26):4293–4300

    Article  CAS  PubMed  Google Scholar 

  • Akritopoulou-Zanze I, Hajduk PJ (2009) Kinase-targeted libraries: the design and synthesis of novel, potent, and selective kinase inhibitors. Drug Discov Today 14(5–6):291–297

    Article  CAS  PubMed  Google Scholar 

  • Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323(5922):1718–1722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alpini G, McGill JM, Larusso NF (2002) The pathobiology of biliary epithelia. Hepatology 35(5):1256–1268

    Article  CAS  PubMed  Google Scholar 

  • Anreddy N, Gupta P, Kathawala RJ, Patel A, Wurpel JN, Chen ZS (2014a) Tyrosine kinase inhibitors as reversal agents for ABC transporter mediated drug resistance. Molecules 19(9):13848–13877

    Article  PubMed  CAS  Google Scholar 

  • Anreddy N, Patel A, Sodani K, Kathawala RJ, Chen EP, Wurpel JND, Chen Z-S (2014b) PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR. Acta Pharm Sin B 4(3):202–207

    Article  PubMed  PubMed Central  Google Scholar 

  • Baselga J, Cervantes A, Martinelli E, Chirivella I, Hoekman K, Hurwitz HI, Jodrell DI, Hamberg P, Casado E, Elvin P, Swaisland A, Iacona R, Tabernero J (2010) Phase I safety, pharmacokinetics, and inhibition of SRC activity study of saracatinib in patients with solid tumors. Clin Cancer Res 16(19):4876–4883

    Article  CAS  PubMed  Google Scholar 

  • Bean J, Riely GJ, Balak M, Marks JL, Ladanyi M, Miller VA, Pao W (2008) Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res 14(22):7519–7525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bellamy F, Bader T, Moussy A, Hermine O (2009) Pharmacokinetics of masitinib in cats. Vet Res Commun 33(8):831–837

    Article  PubMed  Google Scholar 

  • Bhullar J, Natarajan K, Shukla S, Mathias TJ, Sadowska M, Ambudkar SV, Baer MR (2013) The FLT3 inhibitor quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions. PLoS ONE 8(8):e71266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, Monsey J, Goel N, Aronson AB, Li S, Ma CX, Ding L, Mardis ER, Ellis MJ (2013) Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 3(2):224–237

    Article  CAS  PubMed  Google Scholar 

  • Bradeen HA, Eide CA, O’Hare T, Johnson KJ, Willis SG, Lee FY, Druker BJ, Deininger MW (2006) Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood 108(7):2332–2338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Branger J, van den Blink B, Weijer S, Madwed J, Bos CL, Gupta A, Yong CL, Polmar SH, Olszyna DP, Hack CE, van Deventer SJ, Peppelenbosch MP, van der Poll T (2002) Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J Immunol 168(8):4070–4077

    Article  CAS  PubMed  Google Scholar 

  • Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH, Schinkel AH, van Tellingen O, Borst P, Schellens JH (2004) Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug–drug interactions. Cancer Res 64(16):5804–5811

    Article  CAS  PubMed  Google Scholar 

  • Brendel C, Scharenberg C, Dohse M, Robey RW, Bates SE, Shukla S, Ambudkar SV, Wang Y, Wennemuth G, Burchert A, Boudriot U, Neubauer A (2007) Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells. Leukemia 21(6):1267–1275

    Article  CAS  PubMed  Google Scholar 

  • Bruix J, Sherman M, American Association for the Study of Liver D (2011) Management of hepatocellular carcinoma: an update. Hepatology 53(3):1020–1022

    Article  Google Scholar 

  • Burger H, van Tol H, Boersma AW, Brok M, Wiemer EA, Stoter G, Nooter K (2004) Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood 104(9):2940–2942

    Article  CAS  PubMed  Google Scholar 

  • Burris HA 3rd, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O’Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL (2005) Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23(23):5305–5313

    Article  CAS  PubMed  Google Scholar 

  • Calvo E, Tolcher AW, Hammond LA, Patnaik A, de Bono JS, Eiseman IA, Olson SC, Lenehan PF, McCreery H, Lorusso P, Rowinsky EK (2004) Administration of CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, is feasible on a 7-day on, 7-day off schedule: a phase I pharmacokinetic and food effect study. Clin Cancer Res 10(21):7112–7120

    Article  CAS  PubMed  Google Scholar 

  • Campanella NC, de Oliveira AT, Scapulatempo-Neto C, Guimaraes DP, Reis RM (2013) Biomarkers and novel therapeutic targets in gastrointestinal stromal tumors (GISTs). Recent Pat Anticancer Drug Discov 8(3):288–297

    Article  CAS  PubMed  Google Scholar 

  • Carpenter G, Lembach KJ, Morrison MM, Cohen S (1975) Characterization of the binding of 125-I-labeled epidermal growth factor to human fibroblasts. J Biol Chem 250(11):4297–4304

    CAS  PubMed  Google Scholar 

  • Chan F, Sun C, Perumal M, Nguyen QD, Bavetsias V, McDonald E, Martins V, Wilsher NE, Raynaud FI, Valenti M, Eccles S, Te Poele R, Workman P, Aboagye EO, Linardopoulos S (2007) Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity. Mol Cancer Ther 6(12 Pt 1):3147–3157

    Article  CAS  PubMed  Google Scholar 

  • Chee E-C, Lim A, Modamio P, Fernandez-Lastra C, Segarra I (2015) Sunitinib tissue distribution changes after coadministration with ketoconazole in mice. Eur J Drug Metab Pharmacokinet 40:1–11

    Article  CAS  Google Scholar 

  • Chen Y, Tortorici MA, Garrett M, Hee B, Klamerus KJ, Pithavala YK (2013) Clinical pharmacology of axitinib. Clin Pharmacokinet 52(9):713–725

    Article  CAS  PubMed  Google Scholar 

  • Cheng C, Liu ZG, Zhang H, Xie JD, Chen XG, Zhao XQ, Wang F, Liang YJ, Chen LK, Singh S, Chen JJ, Talele TT, Chen ZS, Zhong FT, Fu LW (2012) Enhancing chemosensitivity in ABCB1- and ABCG2-overexpressing cells and cancer stem-like cells by an Aurora kinase inhibitor CCT129202. Mol Pharm 9(7):1971–1982

    Article  CAS  PubMed  Google Scholar 

  • Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G (2007) Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 6(12 Pt 1):3314–3322

    Article  CAS  PubMed  Google Scholar 

  • Chuan Tang S, Nguyen LN, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH (2014) Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer 134(6):1484–1494

    Article  CAS  Google Scholar 

  • Chufan EE, Kapoor K, Sim HM, Singh S, Talele TT, Durell SR, Ambudkar SV (2013) Multiple transport-active binding sites are available for a single substrate on human P-glycoprotein (ABCB1). PLoS ONE 8(12):e82463

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chufan EE, Sim H-M, Ambudkar SV (2015) Chapter three—molecular basis of the polyspecificity of P-glycoprotein (ABCB1): recent biochemical and structural studies. In: John DS, Toshihisa I (eds) Adv Cancer Res, vol 125. Academic Press, pp 71–96

    Google Scholar 

  • Cohen S (1962) Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem 237:1555–1562

    CAS  PubMed  Google Scholar 

  • Cohen S (1965) The stimulation of epidermal proliferation by a specific protein (EGF). Dev Biol 12(3):394–407

    Article  CAS  PubMed  Google Scholar 

  • Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 86(2):695–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cortes JE, Kantarjian HM, Brummendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C (2011) Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 118(17):4567–4576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, Gammon G, Trone D, Armstrong RC, James J, Levis M (2013) Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol 31(29):3681–3687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cowan-Jacob SW, Fendrich G, Floersheimer A, Furet P, Liebetanz J, Rummel G, Rheinberger P, Centeleghe M, Fabbro D, Manley PW (2007) Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr D Biol Crystallogr 63(Pt 1):80–93

    Article  CAS  PubMed  Google Scholar 

  • Coxon A, Bush T, Saffran D, Kaufman S, Belmontes B, Rex K, Hughes P, Caenepeel S, Rottman JB, Tasker A, Patel V, Kendall R, Radinsky R, Polverino A (2009) Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors. Clin Cancer Res 15(1):110–118

    Article  CAS  PubMed  Google Scholar 

  • Coxon A, Ziegler B, Kaufman S, Xu M, Wang H, Weishuhn D, Schmidt J, Sweet H, Starnes C, Saffran D, Polverino A (2012) Antitumor activity of motesanib alone and in combination with cisplatin or docetaxel in multiple human non-small-cell lung cancer xenograft models. Mol Cancer 11:70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cramer J, Kopp S, Bates SE, Chiba P, Ecker GF (2007) Multispecificity of drug transporters: probing inhibitor selectivity for the human drug efflux transporters ABCB1 and ABCG2. ChemMedChem 2(12):1783–1788

    Article  CAS  PubMed  Google Scholar 

  • Cui JJ, Tran-Dube M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP (2011) Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 54(18):6342–6363

    Article  CAS  PubMed  Google Scholar 

  • Cusatis G, Gregorc V, Li J, Spreafico A, Ingersoll RG, Verweij J, Ludovini V, Villa E, Hidalgo M, Sparreboom A, Baker SD (2006) Pharmacogenetics of ABCG2 and adverse reactions to gefitinib. J Natl Cancer Inst 98(23):1739–1742

    Article  CAS  PubMed  Google Scholar 

  • Da Silva CG, Honeywell RJ, Dekker H, Peters GJ (2015) Physicochemical properties of novel protein kinase inhibitors in relation to their substrate specificity for drug transporters. Expert Opin Drug Metab Toxicol 11(5):703–717

    Article  PubMed  CAS  Google Scholar 

  • Dai C-L, Tiwari AK, Wu C-P, Su X-D, Wang S-R, Liu D-G, Ashby CR, Jr., Huang Y, Robey RW, Liang Y-J, Chen L-M, Shi C-J, Ambudkar SV, Chen Z-S, Fu L-W (2008) Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res 68 (19):7905–7914

    Google Scholar 

  • de Boer R, Humblet Y, Wolf J, Nogová L, Ruffert K, Milenkova T, Smith R, Godwood A, Vansteenkiste J (2009) An open-label study of vandetanib with pemetrexed in patients with previously treated non-small-cell lung cancer. Ann Oncol 20(3):486–491

    Article  PubMed  Google Scholar 

  • DeAngelo DJ, Stone RM, Heaney ML, Nimer SD, Paquette RL, Klisovic RB, Caligiuri MA, Cooper MR, Lecerf JM, Karol MD, Sheng S, Holford N, Curtin PT, Druker BJ, Heinrich MC (2006) Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood 108(12):3674–3681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deininger MW (2008) Nilotinib. Clin Cancer Res 14(13):4027–4031

    Article  CAS  PubMed  Google Scholar 

  • Demel MA, Schwaha R, Kramer O, Ettmayer P, Haaksma EE, Ecker GF (2008) In silico prediction of substrate properties for ABC-multidrug transporters. Expert Opin Drug Metab Toxicol 4(9):1167–1180

    Article  CAS  PubMed  Google Scholar 

  • Demetri GD, Wang Y, Wehrle E, Racine A, Nikolova Z, Blanke CD, Joensuu H, von Mehren M (2009) Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 27(19):3141–3147

    Article  CAS  PubMed  Google Scholar 

  • Deng W, Dai CL, Chen JJ, Kathawala RJ, Sun YL, Chen HF, Fu LW, Chen ZS (2013) Tandutinib (MLN518) reverses multidrug resistance by inhibiting the efflux activity of the multidrug resistance protein 7 (ABCC10). Oncol Rep 29(6):2479–2485

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dharmapuri G, Doneti R, Philip GH, Kalle AM (2015) Celecoxib sensitizes imatinib-resistant K562 cells to imatinib by inhibiting MRP1-5, ABCA2 and ABCG2 transporters via Wnt and Ras signaling pathways. Leuk Res 39(7):696–701

    Article  CAS  PubMed  Google Scholar 

  • Dohse M, Scharenberg C, Shukla S, Robey RW, Volkmann T, Deeken JF, Brendel C, Ambudkar SV, Neubauer A, Bates SE (2010) Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab Dispos 38(8):1371–1380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Draft Guidance for Industry: Drug Interaction Studies—Study Design, Data Analysis, Implications for Dosing and Labeling Recommendations (2012) US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)

    Google Scholar 

  • Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344(14):1031–1037

    Article  CAS  PubMed  Google Scholar 

  • Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA, Investigators I (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355(23):2408–2417

    Article  CAS  PubMed  Google Scholar 

  • Durmus S, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH (2012) Oral availability and brain penetration of the B-RAFV600E inhibitor vemurafenib can be enhanced by the P-GLYCOprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Mol Pharm 9(11):3236–3245

    Article  CAS  PubMed  Google Scholar 

  • Durmus S, Hendrikx JJ, Schinkel AH (2015) Apical ABC transporters and cancer chemotherapeutic drug disposition. Adv Cancer Res 125:1–41

    Article  PubMed  Google Scholar 

  • Dvorak HF (2005) Angiogenesis: update 2005. J Thromb Haemost 3(8):1835–1842

    Article  CAS  PubMed  Google Scholar 

  • Ecker GF, Stockner T, Chiba P (2008) Computational models for prediction of interactions with ABC-transporters. Drug Discov Today 13(7–8):311–317

    Article  CAS  PubMed  Google Scholar 

  • Elferink RO, Groen AK (2002) Genetic defects in hepatobiliary transport. Biochim Biophys Acta 1586(2):129–145

    Article  PubMed  Google Scholar 

  • Elkind NB, Szentpetery Z, Apati A, Ozvegy-Laczka C, Varady G, Ujhelly O, Szabo K, Homolya L, Varadi A, Buday L, Keri G, Nemet K, Sarkadi B (2005) Multidrug transporter ABCG2 prevents tumor cell death induced by the epidermal growth factor receptor inhibitor Iressa (ZD1839, Gefitinib). Cancer Res 65(5):1770–1777

    Article  CAS  PubMed  Google Scholar 

  • Erlichman C, Boerner SA, Hallgren CG, Spieker R, Wang XY, James CD, Scheffer GL, Maliepaard M, Ross DD, Bible KC, Kaufmann SH (2001) The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. Cancer Res 61(2):739–748

    CAS  PubMed  Google Scholar 

  • Eskens FA, Steeghs N, Verweij J, Bloem JL, Christensen O, van Doorn L, Ouwerkerk J, de Jonge MJ, Nortier JW, Kraetzschmar J, Rajagopalan P, Gelderblom H (2009) Phase I dose escalation study of telatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 3, platelet-derived growth factor receptor beta, and c-Kit, in patients with advanced or metastatic solid tumors. J Clin Oncol 27(25):4169–4176

    Article  CAS  PubMed  Google Scholar 

  • Faber KN, Muller M, Jansen PL (2003) Drug transport proteins in the liver. Adv Drug Deliv Rev 55(1):107–124

    Article  CAS  PubMed  Google Scholar 

  • Ferreira RJ, dos Santos DJVA, Ferreira M-JU, Guedes RC (2011) Toward a better pharmacophore description of p-glycoprotein modulators, based on macrocyclic diterpenes from euphorbia species. J Chem Inf Model 51(6):1315–1324

    Article  CAS  PubMed  Google Scholar 

  • Ferreira RJ, Ferreira M-JU, dos Santos DJVA (2013) Molecular docking characterizes substrate-binding sites and efflux modulation mechanisms within P-glycoprotein. J Chem Inf Model 53(7):1747–1760

    Article  CAS  PubMed  Google Scholar 

  • Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363(9):809–819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ford JM, Prozialeck WC, Hait WN (1989) Structural features determining activity of phenothiazines and related drugs for inhibition of cell growth and reversal of multidrug resistance. Mol Pharmacol 35(1):105–115

    CAS  PubMed  Google Scholar 

  • Fruman DA, Rommel C (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13(2):140–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fry DW, Kraker AJ, McMichael A, Ambroso LA, Nelson JM, Leopold WR, Connors RW, Bridges AJ (1994) A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 265(5175):1093–1095

    Article  CAS  PubMed  Google Scholar 

  • Gajiwala KS, Feng J, Ferre R, Ryan K, Brodsky O, Weinrich S, Kath JC, Stewart A (2013) Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition. Structure 21(2):209–219

    Article  CAS  PubMed  Google Scholar 

  • Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, Levis M (2014) Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood 123(1):94–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao L, Chen L, Fei XH, Qiu HY, Zhou H, Wang JM (2006) STI571 combined with vincristine greatly suppressed the tumor formation of multidrug-resistant K562 cells in a human-nude mice xenograft model. Chin Med J (Engl) 119(11):911–918

    CAS  Google Scholar 

  • Gazit A, Chen J, App H, McMahon G, Hirth P, Chen I, Levitzki A (1996) Tyrphostins IV–highly potent inhibitors of EGF receptor kinase. Structure-activity relationship study of 4-anilidoquinazolines. Bioorg Med Chem 4(8):1203–1207

    Article  CAS  PubMed  Google Scholar 

  • Geng R, Li J (2015) Apatinib for the treatment of gastric cancer. Expert Opin Pharmacother 16(1):117–122

    Article  CAS  PubMed  Google Scholar 

  • Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743

    Article  CAS  PubMed  Google Scholar 

  • Gongora C (2014) Sorafenib inhibits ABCG2 and overcomes irinotecan resistance–response. Mol Cancer Ther 13(3):764

    Article  CAS  PubMed  Google Scholar 

  • Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JVS, Booth BP, Verbois SL, Morse DE, Liang CY, Chidambaram N, Jiang JX, Tang S, Mahjoob K, Justice R, Pazdur R (2007) Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 13(5):1367–1373

    Article  CAS  PubMed  Google Scholar 

  • Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293(5531):876–880

    Article  CAS  PubMed  Google Scholar 

  • Gozgit JM, Wong MJ, Moran L, Wardwell S, Mohemmad QK, Narasimhan NI, Shakespeare WC, Wang F, Clackson T, Rivera VM (2012) Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol Cancer Ther 11(3):690–699

    Article  CAS  PubMed  Google Scholar 

  • Green TP, Fennell M, Whittaker R, Curwen J, Jacobs V, Allen J, Logie A, Hargreaves J, Hickinson DM, Wilkinson RW, Elvin P, Boyer B, Carragher N, Ple PA, Bermingham A, Holdgate GA, Ward WH, Hennequin LF, Davies BR, Costello GF (2009) Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. Mol Oncol 3(3):248–261

    Article  CAS  PubMed  Google Scholar 

  • Greuber EK, Smith-Pearson P, Wang J, Pendergast AM (2013) Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat Rev Cancer 13(8):559–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grippo JF, Zhang W, Heinzmann D, Yang KH, Wong J, Joe AK, Munster P, Sarapa N, Daud A (2014) A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma. Cancer Chemother Pharmacol 73(1):103–111

    Article  CAS  PubMed  Google Scholar 

  • Guideline on the Investigation of Drug Interactions (2012) European Medicines Agency Committee for Human Medicinal Products. CPMP/EWP/560/95/Rev.1 Corr.2

    Google Scholar 

  • Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364

    Article  CAS  PubMed  Google Scholar 

  • Harris PA, Boloor A, Cheung M, Kumar R, Crosby RM, Davis-Ward RG, Epperly AH, Hinkle KW, Hunter RN 3rd, Johnson JH, Knick VB, Laudeman CP, Luttrell DK, Mook RA, Nolte RT, Rudolph SK, Szewczyk JR, Truesdale AT, Veal JM, Wang L, Stafford JA (2008) Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-b enzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem 51(15):4632–4640

    Article  CAS  PubMed  Google Scholar 

  • He D, Zhao XQ, Chen XG, Fang Y, Singh S, Talele TT, Qiu HJ, Liang YJ, Wang XK, Zhang GQ, Chen ZS, Fu LW (2013) BIRB796, the inhibitor of p38 mitogen-activated protein kinase, enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cells. PLoS ONE 8(1):e54181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hegedus C, Ozvegy-Laczka C, Apati A, Magocsi M, Nemet K, Orfi L, Keri G, Katona M, Takats Z, Varadi A, Szakacs G, Sarkadi B (2009) Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol 158(4):1153–1164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hegedus C, Truta-Feles K, Antalffy G, Varady G, Nemet K, Ozvegy-Laczka C, Keri G, Orfi L, Szakacs G, Settleman J, Varadi A, Sarkadi B (2012) Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib with the ABCG2 multidrug transporter: implications for the emergence and reversal of cancer drug resistance. Biochem Pharmacol 84(3):260–267

    Article  CAS  PubMed  Google Scholar 

  • Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21(23):4342–4349

    Article  CAS  PubMed  Google Scholar 

  • Heinrich MC, Griffith D, McKinley A, Patterson J, Presnell A, Ramachandran A, Debiec-Rychter M (2012) Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clin Cancer Res 18(16):4375–4384

    Article  CAS  PubMed  Google Scholar 

  • Hong DS, Kurzrock R, Mulay M, Rasmussen E, Wu BM, Bass MB, Zhong ZD, Friberg G, Rosen LS (2014) A phase 1b, open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours. Oncotarget 5(22):11154–11167

    Article  PubMed  PubMed Central  Google Scholar 

  • Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E, Traxler P (2004) Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res 64(7):2333–2337

    Article  CAS  PubMed  Google Scholar 

  • Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD (2009) Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res 15(19):6062–6069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu S, Xie G, Zhang DX, Davis C, Long W, Hu Y, Wang F, Kang X, Tan F, Ding L, Wang Y (2012) Synthesis and biological evaluation of crown ether fused quinazoline analogues as potent EGFR inhibitors. Bioorg Med Chem Lett 22(19):6301–6305

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Tang X (2003) Phenotypic determination and characterization of nestin-positive precursors derived from human fetal pancreas. Lab Invest 83(4):539–547

    Article  CAS  PubMed  Google Scholar 

  • Huang Q, Johnson TW, Bailey S, Brooun A, Bunker KD, Burke BJ, Collins MR, Cook AS, Cui JJ, Dack KN, Deal JG, Deng YL, Dinh D, Engstrom LD, He M, Hoffman J, Hoffman RL, Johnson PS, Kania RS, Lam H, Lam JL, Le PT, Li Q, Lingardo L, Liu W, Lu MW, McTigue M, Palmer CL, Richardson PF, Sach NW, Shen H, Smeal T, Smith GL, Stewart AE, Timofeevski S, Tsaparikos K, Wang H, Zhu H, Zhu J, Zou HY, Edwards MP (2014) Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J Med Chem 57(4):1170–1187

    Article  CAS  PubMed  Google Scholar 

  • Hubbard SR, Till JH (2000) Protein tyrosine kinase structure and function. Annu Rev Biochem 69:373–398

    Article  CAS  PubMed  Google Scholar 

  • Humbert M, Castéran N, Letard S, Hanssens K, Iovanna J, Finetti P, Bertucci F, Bader T, Mansfield CD, Moussy A, Hermine O, Dubreuil P (2010) Masitinib combined with standard gemcitabine chemotherapy: in vitro and in vivo studies in human pancreatic tumour cell lines and ectopic mouse model. PLoS ONE 5(3):e9430

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hurwitz HI, Dowlati A, Saini S, Savage S, Suttle AB, Gibson DM, Hodge JP, Merkle EM, Pandite L (2009) Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 15(12):4220–4227

    Article  CAS  PubMed  Google Scholar 

  • Illmer T, Schaich M, Platzbecker U, Freiberg-Richter J, Oelschlagel U, von Bonin M, Pursche S, Bergemann T, Ehninger G, Schleyer E (2004) P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia 18(3):401–408

    Article  CAS  PubMed  Google Scholar 

  • Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA, Lynch T, Johnson BE, Miller VA (2010) Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 28(2):357–360

    Article  CAS  PubMed  Google Scholar 

  • Jahnke W, Grotzfeld RM, Pelle X, Strauss A, Fendrich G, Cowan-Jacob SW, Cotesta S, Fabbro D, Furet P, Mestan J, Marzinzik AL (2010) Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay. J Am Chem Soc 132(20):7043–7048

    Article  CAS  PubMed  Google Scholar 

  • Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, Mahmood U, Mitchell A, Sun Y, Al-Hashem R, Chirieac LR, Padera R, Bronson RT, Kim W, Janne PA, Shapiro GI, Tenen D, Johnson BE, Weissleder R, Sharpless NE, Wong KK (2006) The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 9(6):485–495

    Article  CAS  PubMed  Google Scholar 

  • Jin MS, Oldham ML, Zhang Q, Chen J (2012) Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans. Nature 490(7421):566–569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J, Caponigro G, Hieronymus H, Murray RR, Salehi-Ashtiani K, Hill DE, Vidal M, Zhao JJ, Yang X, Alkan O, Kim S, Harris JL, Wilson CJ, Myer VE, Finan PM, Root DE, Roberts TM, Golub T, Flaherty KT, Dummer R, Weber BL, Sellers WR, Schlegel R, Wargo JA, Hahn WC, Garraway LA (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468(7326):968–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357(20):2040–2048

    Article  CAS  PubMed  Google Scholar 

  • Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354(24):2542–2551

    Article  PubMed  Google Scholar 

  • Kathawala RJ, Chen JJ, Zhang YK, Wang YJ, Patel A, Wang DS, Talele TT, Ashby CR Jr, Chen ZS (2014a) Masitinib antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance. Int J Oncol 44(5):1634–1642

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kathawala RJ, Sodani K, Chen K, Patel A, Abuznait AH, Anreddy N, Sun YL, Kaddoumi A, Ashby CR Jr, Chen ZS (2014b) Masitinib antagonizes ATP-binding cassette subfamily C member 10-mediated paclitaxel resistance: a preclinical study. Mol Cancer Ther 13(3):714–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim EJ, Zalupski MM (2011) Systemic therapy for advanced gastrointestinal stromal tumors: beyond imatinib. J Surg Oncol 104(8):901–906

    Article  CAS  PubMed  Google Scholar 

  • Kitazaki T, Oka M, Tsurutani J, Nakamura Y, Doi S, Yasunaga M, Takemura M, Yabuuchi H, Soda H, Kohno S (2005) Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. Lung Cancer 49(3):337–343

    Article  PubMed  Google Scholar 

  • Knight ZA, Lin H, Shokat KM (2010) Targeting the cancer kinome through polypharmacology. Nat Rev Cancer 10(2):130–137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuang YH, Shen T, Chen X, Sodani K, Hopper-Borge E, Tiwari AK, Lee JW, Fu LW, Chen ZS (2010) Lapatinib and erlotinib are potent reversal agents for MRP7 (ABCC10)-mediated multidrug resistance. Biochem Pharmacol 79(2):154–161

    Article  CAS  PubMed  Google Scholar 

  • Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher KJ, Settleman J, Haber DA (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 102(21):7665–7670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lagas JS, van Waterschoot RA, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH (2010) Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol Cancer Ther 9(2):319–326

    Article  CAS  PubMed  Google Scholar 

  • Le Cesne A, Blay JY, Bui BN, Bouche O, Adenis A, Domont J, Cioffi A, Ray-Coquard I, Lassau N, Bonvalot S, Moussy A, Kinet JP, Hermine O (2010) Phase II study of oral masitinib mesilate in imatinib-naive patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST). Eur J Cancer 46(8):1344–1351

    Article  PubMed  CAS  Google Scholar 

  • Lee YJ, Maeda J, Kusuhara H, Okauchi T, Inaji M, Nagai Y, Obayashi S, Nakao R, Suzuki K, Sugiyama Y, Suhara T (2006) In vivo evaluation of P-glycoprotein function at the blood-brain barrier in nonhuman primates using [11C]verapamil. J Pharmacol Exp Ther 316(2):647–653

    Article  CAS  PubMed  Google Scholar 

  • Lee P, Anderson D, Avrutskaya A, White A, Pheneger T, Winkler J (2009) In vivo activity of ARRY-543, a potent, small molecule inhibitor of EGFR/ErbB-2 in combination with trastuzumab or docetaxel. Cancer Res 69(2 Supplement):2150

    Article  Google Scholar 

  • Lemos C, Kathmann I, Giovannetti E, Calhau C, Jansen G, Peters GJ (2009) Impact of cellular folate status and epidermal growth factor receptor expression on BCRP/ABCG2-mediated resistance to gefitinib and erlotinib. Br J Cancer 100(7):1120–1127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levinson NM, Boxer SG (2012) Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the Abl tyrosine kinase domain. PLoS ONE 7(4):e29828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li C, Alvey C, Bello A, Wilner KD, Tan W (2011) Pharmacokinetics (PK) of crizotinib (PF-02341066) in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumors. ASCO Meet Abst 29 (15):e13065

    Google Scholar 

  • Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, Sun G, Yang Y, Wang L, Xu N, Cheng Y, Wang Z, Zheng L, Tao M, Zhu X, Ji D, Liu X, Yu H (2013) Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol 31(26):3219–3225

    Article  CAS  PubMed  Google Scholar 

  • Li J, Jaimes KF, Aller SG (2014) Refined structures of mouse P-glycoprotein. Protein Sci 23(1):34–46

    Article  PubMed  CAS  Google Scholar 

  • Libermann TA, Razon N, Bartal AD, Yarden Y, Schlessinger J, Soreq H (1984) Expression of epidermal growth factor receptors in human brain tumors. Cancer Res 44(2):753–760

    CAS  PubMed  Google Scholar 

  • Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J (1985a) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313(5998):144–147

    Article  CAS  PubMed  Google Scholar 

  • Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J (1985b) Amplification and overexpression of the EGF receptor gene in primary human glioblastomas. J Cell Sci Suppl 3:161–172

    Article  CAS  PubMed  Google Scholar 

  • Ling J, Johnson KA, Miao Z, Rakhit A, Pantze MP, Hamilton M, Lum BL, Prakash C (2006) Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers. Drug Metab Dispos 34(3):420–426

    CAS  PubMed  Google Scholar 

  • Liu Y, Gray NS (2006) Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2(7):358–364

    Article  CAS  PubMed  Google Scholar 

  • Liu KJ, He JH, Su XD, Sim HM, Xie JD, Chen XG, Wang F, Liang YJ, Singh S, Sodani K, Talele TT, Ambudkar SV, Chen ZS, Wu HY, Fu LW (2013) Saracatinib (AZD0530) is a potent modulator of ABCB1-mediated multidrug resistance in vitro and in vivo. Int J Cancer 132(1):224–235

    Article  CAS  PubMed  Google Scholar 

  • Liu D, Jiang J, Zhang L, Tan F, Wang Y, Zhang D, Hu P (2014) Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects. Cancer Chemother Pharmacol 73(4):721–727

    Article  CAS  PubMed  Google Scholar 

  • Longley DB, Johnston PG (2005) Molecular mechanisms of drug resistance. J Pathol 205(2):275–292

    Article  CAS  PubMed  Google Scholar 

  • Loo TW, Clarke DM (2008) Mutational analysis of ABC proteins. Arch Biochem Biophys 476(1):51–64

    Article  CAS  PubMed  Google Scholar 

  • Lu LD, Stump KL, Wallace NH, Dobrzanski P, Serdikoff C, Gingrich DE, Dugan BJ, Angeles TS, Albom MS, Mason JL, Ator MA, Dorsey BD, Ruggeri BA, Seavey MM (2011) Depletion of autoreactive plasma cells and treatment of lupus nephritis in mice using CEP-33779, a novel, orally active, selective inhibitor of JAK2. J Immunol 187(7):3840–3853

    Article  CAS  PubMed  Google Scholar 

  • Ma SL, Hu YP, Wang F, Huang ZC, Chen YF, Wang XK, Fu LW (2014) Lapatinib antagonizes multidrug resistance-associated protein 1-mediated multidrug resistance by inhibiting its transport function. Mol Med 20:390–399

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, Melo JV (2000) Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 96(3):1070–1079

    CAS  PubMed  Google Scholar 

  • Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, Goldman JM, Melo JV (2003) MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 101(6):2368–2373

    Article  CAS  PubMed  Google Scholar 

  • Maliepaard M, Scheffer GL, Faneyte IF, Van Gastelen MA, Pijnenborg ACLM, Schinkel AH, Van de Vijver MJ, Scheper RJ, Schellens JHM (2001) Subcellular localization and distribution of the Breast Resistance Protein Transporter in normal human tissues. Cancer Res 61(8):3458–3464

    CAS  PubMed  Google Scholar 

  • Manley PW, Cowan-Jacob SW, Mestan J (2005) Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochim Biophys Acta 1754(1–2):3–13

    Article  CAS  PubMed  Google Scholar 

  • Marchetti S, de Vries NA, Buckle T, Bolijn MJ, van Eijndhoven MA, Beijnen JH, Mazzanti R, van Tellingen O, Schellens JH (2008) Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice. Mol Cancer Ther 7(8):2280–2287

    Article  CAS  PubMed  Google Scholar 

  • Mathias TJ, Natarajan K, Shukla S, Doshi KA, Singh ZN, Ambudkar SV, Baer MR (2015) The FLT3 and PDGFR inhibitor crenolanib is a substrate of the multidrug resistance protein ABCB1 but does not inhibit transport function at pharmacologically relevant concentrations. Invest New Drugs 33(2):300–309

    Article  CAS  PubMed  Google Scholar 

  • McDermott U, Iafrate AJ, Gray NS, Shioda T, Classon M, Maheswaran S, Zhou W, Choi HG, Smith SL, Dowell L, Ulkus LE, Kuhlmann G, Greninger P, Christensen JG, Haber DA, Settleman J (2008) Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 68(9):3389–3395

    Article  CAS  PubMed  Google Scholar 

  • McTigue M, Murray BW, Chen JH, Deng YL, Solowiej J, Kania RS (2012) Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc Natl Acad Sci USA 109(45):18281–18289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mi Y, Lou L (2007) ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein. Br J Cancer 97(7):934–940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mi YJ, Liang YJ, Huang HB, Zhao HY, Wu CP, Wang F, Tao LY, Zhang CZ, Dai CL, Tiwari AK, Ma XX, To KK, Ambudkar SV, Chen ZS, Fu LW (2010) Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters. Cancer Res 70(20):7981–7991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Midgley RS, Kerr DJ, Flaherty KT, Stevenson JP, Pratap SE, Koch KM, Smith DA, Versola M, Fleming RA, Ward C, O’Dwyer PJ, Middleton MR (2007) A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan. Ann Oncol 18(12):2025–2029

    Article  CAS  PubMed  Google Scholar 

  • Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357(26):2666–2676

    Article  CAS  PubMed  Google Scholar 

  • Minocha M, Khurana V, Qin B, Pal D, Mitra AK (2012a) Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib. Int J Pharm 436(1–2):127–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minocha M, Khurana V, Qin B, Pal D, Mitra AK (2012b) Co-administration strategy to enhance brain accumulation of vandetanib by modulating P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp1/Abcg2) mediated efflux with m-TOR inhibitors. Int J Pharm 434(1–2):306–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mittapalli RK, Vaidhyanathan S, Sane R, Elmquist WF (2012) Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032). J Pharmacol Exp Ther 342(1):33–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizuno T, Fukudo M, Fukuda T, Terada T, Dong M, Kamba T, Yamasaki T, Ogawa O, Katsura T, Inui K, Vinks AA, Matsubara K (2014) The effect of ABCG2 genotype on the population pharmacokinetics of sunitinib in patients with renal cell carcinoma. Ther Drug Monit 36(3):310–316

    Article  CAS  PubMed  Google Scholar 

  • Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH, Eliseenkova AV, Green D, Schlessinger J, Hubbard SR (1998) Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J 17(20):5896–5904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mol CD, Fabbro D, Hosfield DJ (2004) Structural insights into the conformational selectivity of STI-571 and related kinase inhibitors. Curr Opin Drug Discov Devel 7(5):639–648

    CAS  PubMed  Google Scholar 

  • Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W, Institute National Cancer, National Cancer Institute of Canada Clinical Trials G (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25(15):1960–1966

    Article  CAS  PubMed  Google Scholar 

  • Mulvihill MJ, Cooke A, Rosenfeld-Franklin M, Buck E, Foreman K, Landfair D, O’Connor M, Pirritt C, Sun Y, Yao Y, Arnold LD, Gibson NW, Ji QS (2009) Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med Chem 1(6):1153–1171

    Article  CAS  PubMed  Google Scholar 

  • Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J (2002) Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 62(15):4236–4243

    CAS  PubMed  Google Scholar 

  • Natarajan K, Bhullar J, Shukla S, Burcu M, Chen ZS, Ambudkar SV, Baer MR (2013) The Pim kinase inhibitor SGI-1776 decreases cell surface expression of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and drug transport by Pim-1-dependent and -independent mechanisms. Biochem Pharmacol 85(4):514–524

    Article  CAS  PubMed  Google Scholar 

  • Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468(7326):973–977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niwakawa M, Yamaguchi R, Onozawa Y, Yasui H, Taku K, Naito T, Akinaga S, Boku N, Yamamoto N (2013) Phase I study of highly selective inhibitor of VEGFR tyrosine kinase, tivozanib, in Japanese patients with solid tumors. Cancer Sci 104(8):1039–1044

    Article  CAS  PubMed  Google Scholar 

  • Oberoi RK, Mittapalli RK, Elmquist WF (2013) Pharmacokinetic assessment of efflux transport in sunitinib distribution to the brain. J Pharmacol Exp Ther 347(3):755–764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol 7(5):359–371

    Article  CAS  PubMed  Google Scholar 

  • Osherov N, Levitzki A (1994) Epidermal-growth-factor-dependent activation of the src-family kinases. Eur J Biochem 225(3):1047–1053

    Article  CAS  PubMed  Google Scholar 

  • Ostronoff F, Estey E (2013) The role of quizartinib in the treatment of acute myeloid leukemia. Expert Opin Investig Drugs 22(12):1659–1669

    Article  CAS  PubMed  Google Scholar 

  • Ozvegy-Laczka C, Hegedus T, Varady G, Ujhelly O, Schuetz JD, Varadi A, Keri G, Orfi L, Nemet K, Sarkadi B (2004) High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol 65(6):1485–1495

    Article  PubMed  Google Scholar 

  • Pajeva IK, Globisch C, Wiese M (2009) Combined pharmacophore modeling, docking, and 3D QSAR studies of ABCB1 and ABCC1 transporter inhibitors. ChemMedChem 4(11):1883–1896

    Article  CAS  PubMed  Google Scholar 

  • Pao W, Chmielecki J (2010) Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 10(11):760–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, DeLong L, Silliman N, Ptak J, Szabo S, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Lengauer C, Velculescu VE (2005) Colorectal cancer: mutations in a signalling pathway. Nature 436(7052):792

    Article  CAS  PubMed  Google Scholar 

  • Patel A, Tiwari AK, Chufan EE, Sodani K, Anreddy N, Singh S, Ambudkar SV, Stephani R, Chen ZS (2013) PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells. Cancer Chemother Pharmacol 72(1):189–199

    Article  CAS  PubMed  Google Scholar 

  • Pearce HL, Safa AR, Bach NJ, Winter MA, Cirtain MC, Beck WT (1989) Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance. Proc Natl Acad Sci USA 86(13):5128–5132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng XX, Tiwari AK, Wu HC, Chen ZS (2012) Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells. Chin J Cancer 31(2):110–118

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pleban K, Kopp S, Csaszar E, Peer M, Hrebicek T, Rizzi A, Ecker GF, Chiba P (2005) P-Glycoprotein substrate binding domains are located at the transmembrane domain/transmembrane domain interfaces: a combined photoaffinity labeling-protein homology modeling approach. Mol Pharmacol 67(2):365–374

    Article  CAS  PubMed  Google Scholar 

  • Poller B, Wagenaar E, Tang SC, Schinkel AH (2011) Double-transduced MDCKII cells to study human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) interplay in drug transport across the blood-brain barrier. Mol Pharm 8(2):571–582

    Article  CAS  PubMed  Google Scholar 

  • Polli JW, Humphreys JE, Harmon KA, Castellino S, O’Mara MJ, Olson KL, John-Williams LS, Koch KM, Serabjit-Singh CJ (2008) The role of efflux and uptake transporters in [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metab Dispos 36(4):695–701

    Article  CAS  PubMed  Google Scholar 

  • Polverino A, Coxon A, Starnes C, Diaz Z, DeMelfi T, Wang L, Bready J, Estrada J, Cattley R, Kaufman S, Chen D, Gan Y, Kumar G, Meyer J, Neervannan S, Alva G, Talvenheimo J, Montestruque S, Tasker A, Patel V, Radinsky R, Kendall R (2006) AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 66(17):8715–8721

    Article  CAS  PubMed  Google Scholar 

  • Qiu C, Tarrant MK, Choi SH, Sathyamurthy A, Bose R, Banjade S, Pal A, Bornmann WG, Lemmon MA, Cole PA, Leahy DJ (2008) Mechanism of activation and inhibition of the HER4/ErbB4 kinase. Structure 16(3):460–467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A (2004) Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 64(11):3958–3965

    Article  CAS  PubMed  Google Scholar 

  • Reis M, Ferreira RJ, Santos MMM, dos Santos DJVA, Molnár J, Ferreira M-JU (2013) Enhancing macrocyclic diterpenes as multidrug-resistance reversers: structure-activity studies on jolkinol D derivatives. J Med Chem 56(3):748–760

    Article  CAS  PubMed  Google Scholar 

  • Ren Z, Zhu K, Kang H, Lu M, Qu Z, Lu L, Song T, Zhou W, Wang H, Yang W, Wang X, Yang Y, Shi L, Bai Y, Guo X, Ye SL (2015) Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin Oncol 33(8):894–900

    Article  CAS  PubMed  Google Scholar 

  • Reyner EL, Sevidal S, West MA, Clouser-Roche A, Freiwald S, Fenner K, Ullah M, Lee CA, Smith BJ (2013) In vitro characterization of axitinib interactions with human efflux and hepatic uptake transporters: implications for disposition and drug interactions. Drug Metab Dispos 41(8):1575–1583

    Article  CAS  PubMed  Google Scholar 

  • Rumpold H, Wolf AM, Gruenewald K, Gastl G, Gunsilius E, Wolf D (2005) RNAi-mediated knockdown of P-glycoprotein using a transposon-based vector system durably restores imatinib sensitivity in imatinib-resistant CML cell lines. Exp Hematol 33(7):767–775

    Article  CAS  PubMed  Google Scholar 

  • Ryoo S, Choi J, Kim J, Bae S, Hong J, Jo S, Kim S, Lee Y (2013) BIRB 796 has distinctive anti-inflammatory effects on different cell types. Immune Netw 13(6):283–288

    Article  PubMed  PubMed Central  Google Scholar 

  • Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550

    Article  CAS  PubMed  Google Scholar 

  • Seavey MM, Lu LD, Stump KL, Wallace NH, Hockeimer W, O’Kane TM, Ruggeri BA, Dobrzanski P (2012) Therapeutic efficacy of CEP-33779, a novel selective JAK2 inhibitor, in a mouse model of colitis-induced colorectal cancer. Mol Cancer Ther 11(4):984–993

    Article  CAS  PubMed  Google Scholar 

  • Seelig A (1998a) How does P-glycoprotein recognize its substrates? Int J Clin Pharmacol Ther 36(1):50–54

    CAS  PubMed  Google Scholar 

  • Seelig A (1998b) A general pattern for substrate recognition by P-glycoprotein. Eur J Biochem 251(1–2):252–261

    Article  CAS  PubMed  Google Scholar 

  • Seeliger MA, Nagar B, Frank F, Cao X, Henderson MN, Kuriyan J (2007) c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty. Structure 15(3):299–311

    Article  CAS  PubMed  Google Scholar 

  • Sen R, Natarajan K, Bhullar J, Shukla S, Fang HB, Cai L, Chen ZS, Ambudkar SV, Baer MR (2012) The novel BCR-ABL and FLT3 inhibitor ponatinib is a potent inhibitor of the MDR-associated ATP-binding cassette transporter ABCG2. Mol Cancer Ther 11(9):2033–2044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305(5682):399–401

    Article  CAS  PubMed  Google Scholar 

  • Shapiro AB, Ling V (1997) Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur J Biochem 250(1):130–137

    Article  CAS  PubMed  Google Scholar 

  • Shen T, Kuang YH, Ashby CR, Lei Y, Chen A, Zhou Y, Chen X, Tiwari AK, Hopper-Borge E, Ouyang J, Chen ZS (2009) Imatinib and nilotinib reverse multidrug resistance in cancer cells by inhibiting the efflux activity of the MRP7 (ABCC10). PLoS ONE 4(10):e7520

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L, National Cancer Institute of Canada Clinical Trials G (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353 (2):123–132

    Google Scholar 

  • Shi Z, Peng XX, Kim IW, Shukla S, Si QS, Robey RW, Bates SE, Shen T, Ashby CR Jr, Fu LW, Ambudkar SV, Chen ZS (2007) Erlotinib (Tarceva, OSI-774) antagonizes ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance. Cancer Res 67(22):11012–11020

    Article  CAS  PubMed  Google Scholar 

  • Shi Z, Tiwari AK, Shukla S, Robey RW, Kim IW, Parmar S, Bates SE, Si QS, Goldblatt CS, Abraham I, Fu LW, Ambudkar SV, Chen ZS (2009) Inhibiting the function of ABCB1 and ABCG2 by the EGFR tyrosine kinase inhibitor AG1478. Biochem Pharmacol 77(5):781–793

    Article  CAS  PubMed  Google Scholar 

  • Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y (2013) Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol 14(10):953–961

    Article  CAS  PubMed  Google Scholar 

  • Shimamura T, Ji H, Minami Y, Thomas RK, Lowell AM, Shah K, Greulich H, Glatt KA, Meyerson M, Shapiro GI, Wong KK (2006) Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272. Cancer Res 66(13):6487–6491

    Article  CAS  PubMed  Google Scholar 

  • Shukla S, Sauna ZE, Ambudkar SV (2008a) Evidence for the interaction of imatinib at the transport-substrate site(s) of the multidrug-resistance-linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. Leukemia 22(2):445–447

    Article  CAS  PubMed  Google Scholar 

  • Shukla S, Wu CP, Ambudkar SV (2008b) Development of inhibitors of ATP-binding cassette drug transporters: present status and challenges. Expert Opin Drug Metab Toxicol 4(2):205–223

    Article  CAS  PubMed  Google Scholar 

  • Shukla S, Robey RW, Bates SE, Ambudkar SV (2009) Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2. Drug Metab Dispos 37(2):359–365

    Article  CAS  PubMed  Google Scholar 

  • Shukla S, Skoumbourdis AP, Walsh MJ, Hartz AM, Fung KL, Wu CP, Gottesman MM, Bauer B, Thomas CJ, Ambudkar SV (2011) Synthesis and characterization of a BODIPY conjugate of the BCR-ABL kinase inhibitor Tasigna (nilotinib): evidence for transport of Tasigna and its fluorescent derivative by ABC drug transporters. Mol Pharm 8(4):1292–1302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shukla S, Chen ZS, Ambudkar SV (2012) Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance. Drug Resist Updat 15(1–2):70–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shukla S, Chufan EE, Singh S, Skoumbourdis AP, Kapoor K, Boxer MB, Duveau DY, Thomas CJ, Talele TT, Ambudkar SV (2014) Elucidation of the structural basis of interaction of the BCR-ABL kinase inhibitor, nilotinib (Tasigna) with the human ABC drug transporter P-glycoprotein. Leukemia 28(4):961–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sodani K, Patel A, Anreddy N, Singh S, Yang DH, Kathawala RJ, Kumar P, Talele TT, Chen ZS (2014) Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo. Biochem Pharmacol 89(1):52–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C, Kraemer O, Himmelsbach F, Haaksma E, Adolf GR (2012) Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 343(2):342–350

    Article  CAS  PubMed  Google Scholar 

  • Sparreboom A, Loos WJ, Burger H, Sissung TM, Verweij J, Figg WD, Nooter K, Gelderblom H (2005) Effect of ABCG2 genotype on the oral bioavailability of topotecan. Cancer Biol Ther 4(6):650–658

    Article  CAS  PubMed  Google Scholar 

  • Stamos J, Sliwkowski MX, Eigenbrot C (2002) Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 277(48):46265–46272

    Article  CAS  PubMed  Google Scholar 

  • Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28(6):1061–1068

    Article  CAS  PubMed  Google Scholar 

  • Strumberg D, Schultheis B, Adamietz IA, Christensen O, Buechert M, Kraetzschmar J, Rajagopalan P, Ludwig M, Frost A, Steinbild S, Scheulen ME, Mross K (2008) Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours. Br J Cancer 99(10):1579–1585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun YL, Kumar P, Sodani K, Patel A, Pan Y, Baer MR, Chen ZS, Jiang WQ (2014) Ponatinib enhances anticancer drug sensitivity in MRP7-overexpressing cells. Oncol Rep 31(4):1605–1612

    CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki T, Fukazawa N, San-nohe K, Sato W, Yano O, Tsuruo T (1997) Structure-activity relationship of newly synthesized quinoline derivatives for reversal of multidrug resistance in cancer. J Med Chem 40(13):2047–2052

    Article  CAS  PubMed  Google Scholar 

  • Swaisland HC, Smith RP, Laight A, Kerr DJ, Ranson M, Wilder-Smith CH, Duvauchelle T (2005) Single-dose clinical pharmacokinetic studies of gefitinib. Clin Pharmacokinet 44(11):1165–1177

    Article  CAS  PubMed  Google Scholar 

  • Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O’Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL (2006) Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354(24):2531–2541

    Article  CAS  PubMed  Google Scholar 

  • Tan CS, Hobson-Peters JM, Stoermer MJ, Fairlie DP, Khromykh AA, Hall RA (2013) An interaction between the methyltransferase and RNA dependent RNA polymerase domains of the West Nile virus NS5 protein. J Gen Virol 94(Pt 9):1961–1971

    Article  CAS  PubMed  Google Scholar 

  • Tang SC, Lagas JS, Lankheet NA, Poller B, Hillebrand MJ, Rosing H, Beijnen JH, Schinkel AH (2012) Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration. Int J Cancer 130(1):223–233

    Article  CAS  PubMed  Google Scholar 

  • Tang SJ, Chen LK, Wang F, Zhang YK, Huang ZC, To KK, Wang XK, Talele TT, Chen ZS, Chen WQ, Fu LW (2014) CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function. Biochem Pharmacol 91(2):144–156

    Article  CAS  PubMed  Google Scholar 

  • Tao LY, Liang YJ, Wang F, Chen LM, Yan YY, Dai CL, Fu LW (2009) Cediranib (recentin, AZD2171) reverses ABCB1- and ABCC1-mediated multidrug resistance by inhibition of their transport function. Cancer Chemother Pharmacol 64(5):961–969

    Article  CAS  PubMed  Google Scholar 

  • Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84(21):7735–7738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas F, Rochaix P, White-Koning M, Hennebelle I, Sarini J, Benlyazid A, Malard L, Lefebvre JL, Chatelut E, Delord JP (2009) Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma. Eur J Cancer 45(13):2316–2323

    Article  CAS  PubMed  Google Scholar 

  • Tiwari AK, Sodani K, Wang SR, Kuang YH, Ashby CR Jr, Chen X, Chen ZS (2009) Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol 78(2):153–161

    Article  CAS  PubMed  Google Scholar 

  • Tiwari AK, Sodani K, Dai CL, Abuznait AH, Singh S, Xiao ZJ, Patel A, Talele TT, Fu L, Kaddoumi A, Gallo JM, Chen ZS (2013) Nilotinib potentiates anticancer drug sensitivity in murine ABCB1-, ABCG2-, and ABCC10-multidrug resistance xenograft models. Cancer Lett 328(2):307–317

    Article  CAS  PubMed  Google Scholar 

  • Tokarski JS, Newitt JA, Chang CYJ, Cheng JD, Wittekind M, Kiefer SE, Kish K, Lee FYF, Borzillerri R, Lombardo LJ, Xie D, Zhang Y, Klei HE (2006) The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 66(11):5790–5797

    Article  CAS  PubMed  Google Scholar 

  • Tsou HR, Overbeek-Klumpers EG, Hallett WA, Reich MF, Floyd MB, Johnson BD, Michalak RS, Nilakantan R, Discafani C, Golas J, Rabindran SK, Shen R, Shi X, Wang YF, Upeslacis J, Wissner A (2005) Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem 48(4):1107–1131

    Article  CAS  PubMed  Google Scholar 

  • Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, Lee J, Yarden Y, Libermann TA, Schlessinger J et al (1984) Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309(5967):418–425

    Article  CAS  PubMed  Google Scholar 

  • van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schoffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P, Tissue ES, Bone Sarcoma G, group Ps (2012) Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379(9829):1879–1886

    Article  PubMed  CAS  Google Scholar 

  • Verslype C, Rosmorduc O, Rougier P, Group EGW (2012) Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 23(7):vii41–48

    Google Scholar 

  • Wakeling AE, Barker AJ, Davies DH, Brown DS, Green LR, Cartlidge SA, Woodburn JR (1996) Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines. Breast Cancer Res Treat 38(1):67–73

    Article  CAS  PubMed  Google Scholar 

  • Wang F, Mi YJ, Chen XG, Wu XP, Liu Z, Chen SP, Liang YJ, Cheng C, To KK, Fu LW (2012a) Axitinib targeted cancer stemlike cells to enhance efficacy of chemotherapeutic drugs via inhibiting the drug transport function of ABCG2. Mol Med 18:887–898

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang T, Agarwal S, Elmquist WF (2012b) Brain distribution of cediranib is limited by active efflux at the blood-brain barrier. J Pharmacol Exp Ther 341(2):386–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang XK, He JH, Xu JH, Ye S, Wang F, Zhang H, Huang ZC, To KK, Fu LW (2014a) Afatinib enhances the efficacy of conventional chemotherapeutic agents by eradicating cancer stem-like cells. Cancer Res 74(16):4431–4445

    Article  CAS  PubMed  Google Scholar 

  • Wang XK, To KK, Huang LY, Xu JH, Yang K, Wang F, Huang ZC, Ye S, Fu LW (2014b) Afatinib circumvents multidrug resistance via dually inhibiting ATP binding cassette subfamily G member 2 in vitro and in vivo. Oncotarget 5(23):11971–11985

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang DS, Patel A, Sim HM, Zhang YK, Wang YJ, Kathawala RJ, Zhang H, Talele TT, Ambudkar SV, Xu RH, Chen ZS (2014c) ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2. J Cell Biochem 115(8):1381–1391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang YJ, Kathawala RJ, Zhang YK, Patel A, Kumar P, Shukla S, Fung KL, Ambudkar SV, Talele TT, Chen ZS (2014d) Motesanib (AMG706), a potent multikinase inhibitor, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1. Biochem Pharmacol 90(4):367–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ward WH, Cook PN, Slater AM, Davies DH, Holdgate GA, Green LR (1994) Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. Biochem Pharmacol 48(4):659–666

    Article  CAS  PubMed  Google Scholar 

  • Ward AB, Szewczyk P, Grimard V, Lee CW, Martinez L, Doshi R, Caya A, Villaluz M, Pardon E, Cregger C, Swartz DJ, Falson PG, Urbatsch IL, Govaerts C, Steyaert J, Chang G (2013) Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain. Proc Natl Acad Sci USA 110(33):13386–13391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei L, Huang N, Yang L, Zheng DY, Cui YZ, Li AM, Lu CW, Zheng H (1023) Luo RC (2009) [Sorafenib reverses multidrug resistance of hepatoma cells in vitro]. Nan Fang Yi Ke Da Xue Xue Bao 29(5):1016–1019

    Google Scholar 

  • Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E, Kung AL, Mestan J, Daley GQ, Callahan L, Catley L, Cavazza C, Azam M, Neuberg D, Wright RD, Gilliland DG, Griffin JD (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7(2):129–141

    Article  CAS  PubMed  Google Scholar 

  • Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD (2006) AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer 94(12):1765–1769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wind S, Schmid M, Erhardt J, Goeldner RG, Stopfer P (2013) Pharmacokinetics of afatinib, a selective irreversible ErbB family blocker, in patients with advanced solid tumours. Clin Pharmacokinet 52(12):1101–1109

    Article  CAS  PubMed  Google Scholar 

  • Wong KK, Fracasso PM, Bukowski RM, Lynch TJ, Munster PN, Shapiro GI, Janne PA, Eder JP, Naughton MJ, Ellis MJ, Jones SF, Mekhail T, Zacharchuk C, Vermette J, Abbas R, Quinn S, Powell C, Burris HA (2009) A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res 15(7):2552–2558

    Article  CAS  PubMed  Google Scholar 

  • Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L (2004) A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 64(18):6652–6659

    Article  CAS  PubMed  Google Scholar 

  • Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B (2007) The genomic landscapes of human breast and colorectal cancers. Science 318(5853):1108–1113

    Article  CAS  PubMed  Google Scholar 

  • Wu C-PV, Ambudkar S (2014) The pharmacological impact of ATP-binding cassette drug transporters on vemurafenib-based therapy. Acta Pharm Sin B 4(2):105–111

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu CP, Sim HM, Huang YH, Liu YC, Hsiao SH, Cheng HW, Li YQ, Ambudkar SV, Hsu SC (2013) Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells. Biochem Pharmacol 85(3):325–334

    Article  CAS  PubMed  Google Scholar 

  • Xiang QF, Wang F, Su XD, Liang YJ, Zheng LS, Mi YJ, Chen WQ, Fu LW (2011) Effect of BIBF 1120 on reversal of ABCB1-mediated multidrug resistance. Cell Oncol (Dordr) 34(1):33–44

    Article  CAS  Google Scholar 

  • Xie Y, Burcu M, Linn DE, Qiu Y, Baer MR (2010) Pim-1 kinase protects P-glycoprotein from degradation and enables its glycosylation and cell surface expression. Mol Pharmacol 78(2):310–318

    Article  CAS  PubMed  Google Scholar 

  • Yamakawa Y, Hamada A, Shuto T, Yuki M, Uchida T, Kai H, Kawaguchi T, Saito H (2011) Pharmacokinetic impact of SLCO1A2 polymorphisms on imatinib disposition in patients with chronic myeloid leukemia. Clin Pharmacol Ther 90(1):157–163

    Article  CAS  PubMed  Google Scholar 

  • Yanase K, Tsukahara S, Asada S, Ishikawa E, Imai Y, Sugimoto Y (2004) Gefinitib reverses breast cancer resistance protein-mediated drug resistance. Mol Cancer Ther 3(9):1119–1125

    CAS  PubMed  Google Scholar 

  • Yang JJ, Milton MN, Yu S, Liao M, Liu N, Wu JT, Gan L, Balani SK, Lee FW, Prakash S, Xia CQ (2010) P-glycoprotein and breast cancer resistance protein affect disposition of tandutinib, a tyrosine kinase inhibitor. Drug Metab Lett 4(4):201–212

    Article  PubMed  Google Scholar 

  • Yang D, Kathawala RJ, Chufan EE, Patel A, Ambudkar SV, Chen ZS, Chen X (2014) Tivozanib reverses multidrug resistance mediated by ABCB1 (P-glycoprotein) and ABCG2 (BCRP). Future Oncol 10(11):1827–1841

    Article  CAS  PubMed  Google Scholar 

  • Yoshikawa S, Kukimoto-Niino M, Parker L, Handa N, Terada T, Fujimoto T, Terazawa Y, Wakiyama M, Sato M, Sano S, Kobayashi T, Tanaka T, Chen L, Liu ZJ, Wang BC, Shirouzu M, Kawa S, Semba K, Yamamoto T, Yokoyama S (2013) Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor. Oncogene 32(1):27–38

    Article  CAS  PubMed  Google Scholar 

  • Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ (2008) The T790 M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 105(6):2070–2075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zandvliet M, Teske E, Chapuis T, Fink-Gremmels J, Schrickx JA (2013) Masitinib reverses doxorubicin resistance in canine lymphoid cells by inhibiting the function of P-glycoprotein. J Vet Pharmacol Ther 36(6):583–587

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Adrian FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo GR, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu G, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS (2010) Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463(7280):501–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Wang YJ, Zhang YK, Wang DS, Kathawala RJ, Patel A, Talele TT, Chen ZS, Fu LW (2014a) AST1306, a potent EGFR inhibitor, antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance. Cancer Lett 350(1–2):61–68

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Kathawala RJ, Wang YJ, Zhang YK, Patel A, Shukla S, Robey RW, Talele TT, Ashby CR Jr, Ambudkar SV, Bates SE, Fu LW, Chen ZS (2014b) Linsitinib (OSI-906) antagonizes ATP-binding cassette subfamily G member 2 and subfamily C member 10-mediated drug resistance. Int J Biochem Cell Biol 51:111–119

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Cao J, Li J, Zhang Y, Chen Z, Peng W, Sun S, Zhao N, Wang J, Zhong D, Zhang X, Zhang J (2014c) A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors. J Hematol Oncol 7:22

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhao XQ, Xie JD, Chen XG, Sim HM, Zhang X, Liang YJ, Singh S, Talele TT, Sun Y, Ambudkar SV, Chen ZS, Fu LW (2012) Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo. Mol Pharmacol 82(1):47–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao XQ, Dai CL, Ohnuma S, Liang YJ, Deng W, Chen JJ, Zeng MS, Ambudkar SV, Chen ZS, Fu LW (2013) Tandutinib (MLN518/CT53518) targeted to stem-like cells by inhibiting the function of ATP-binding cassette subfamily G member 2. Eur J Pharm Sci 49(3):441–450

    Article  CAS  PubMed  Google Scholar 

  • Zheng LS, Wang F, Li YH, Zhang X, Chen LM, Liang YJ, Dai CL, Yan YY, Tao LY, Mi YJ, Yang AK, To KK, Fu LW (2009) Vandetanib (Zactima, ZD6474) antagonizes ABCC1- and ABCG2-mediated multidrug resistance by inhibition of their transport function. PLoS ONE 4(4):e5172

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou T, Commodore L, Huang WS, Wang Y, Thomas M, Keats J, Xu Q, Rivera VM, Shakespeare WC, Clackson T, Dalgarno DC, Zhu X (2011) Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem Biol Drug Des 77(1):1–11

    Article  CAS  PubMed  Google Scholar 

  • Zhou WJ, Zhang X, Cheng C, Wang F, Wang XK, Liang YJ, To KK, Zhou W, Huang HB, Fu LW (2012) Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein. Br J Pharmacol 166(5):1669–1683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank George Leiman for editing the manuscript and Dr. Eduardo Chufan for help with Fig. 3. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

Conflict of interest disclosure

The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892-4256, USA

    Suneet Shukla, Atish Patel & Suresh V. Ambudkar

Authors
  1. Suneet Shukla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Atish Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suresh V. Ambudkar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suresh V. Ambudkar .

Editor information

Editors and Affiliations

  1. School of Life Sciences, University of Technology, Sydney, Australia

    Anthony M. George

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Shukla, S., Patel, A., Ambudkar, S.V. (2016). Mechanistic and Pharmacological Insights into Modulation of ABC Drug Transporters by Tyrosine Kinase Inhibitors. In: George, A. (eds) ABC Transporters - 40 Years on. Springer, Cham. https://doi.org/10.1007/978-3-319-23476-2_10

Download citation

Publish with us

Policies and ethics

Search

Navigation