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The Mitogen-Activated Protein Kinase Pathway for Molecular-Targeted Cancer Treatment

  • Chapter
Targeted Interference with Signal Transduction Events

Part of the book series: Resent Results in Cancer Research ((RECENTCANCER,volume 172))

Abstract

The molecular characterization of key events associated with tumor initiation and progression has led to the identification of cellular signaling pathways that contribute not only to normal cell functioning but also to the overall phenotype associated with cancer. One such example is the Ras-regulated kinase pathway. This signaling module, comprising Raf, mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK), plays a central role in regulating a broad range of cellular events. In response to a diverse group of extracellular stimuli including growth factors, cytokines, and protooncogenes, activation of this pathway results in alterations in cell proliferation, differentiation, and survival. It is therefore not surprising that this pathway has been found to be upregulated in a large percentage of human tumors. While contributing to the uncontrolled growth and enhanced survival of tumor cells, the Ras-MAP kinase pathway also plays a key role in their metastatic spread by regulating cell motility and invasion.

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References

  • Ahn NG, Nahreini TS, Tolwinski NS, Resing KA (2001) Pharmacological inhibitors of MKK1 and MKK2. Methods Enzymol 332:417–431

    Article  PubMed  CAS  Google Scholar 

  • Allen LF, Sebolt-Leopold J, Meyer MB (2003) CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol 30:105–116

    Article  PubMed  CAS  Google Scholar 

  • Alessi DR, Saito Y, Campbell DG, Cohen P, Sithanaandam G, Rapp U, Ashwort A, Marshall C, Cowley S (1994) Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. EMBO J 13:1610–1619

    PubMed  CAS  Google Scholar 

  • Baccarini M (2005) Second nature: biological functions of the Raf-1 “kinase”. FEBS Lett 579:3271–327

    Article  PubMed  CAS  Google Scholar 

  • Beeram M, Patnaik A, Rowinsky EK (2005) Raf:a strategic target for therapeutic development against cancer. J Clin Oncol 23:6771–6790

    Article  PubMed  CAS  Google Scholar 

  • Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, Joshi MB, Harpole D, Lancaster JM, Berchuck A, Olson JA Jr, Marks JR, Dressman HK, West M, Nevins JR (2006) Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439:353–357

    Article  PubMed  CAS  Google Scholar 

  • Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and-independent mechanisms. Science 286:1358–1362

    Article  PubMed  CAS  Google Scholar 

  • Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, Roth JA, Albelda SM, Davies H, Cox C, Brignell G, Stephens P, Futreal PA, Wooster R, Stratton MR, Weber BL (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62:6997–7000

    PubMed  CAS  Google Scholar 

  • Brott BK, Alessandrini A, Largaespada DA, Copeland NG, Jenkins NA, Crews CM, Erikson RL (1993) MEK2 is a kinase related MEK1 and is differentially expressed in murine tissues. Cell Growth Differ 4:921–929

    PubMed  CAS  Google Scholar 

  • Busca R, Abbe P, Mantoux F, Aberdam E, Peyssonnaux C, Eychene A, Ortonne JP, Ballotti R (2000) Ras mediates the cAMP-dependent activation of extracellular signal-regulated kinases (ERKs) in melanocytes. EMBO J 19:2900–2910

    Article  PubMed  CAS  Google Scholar 

  • Catling AD, Schaeffer HJ, Reuter CW, Reddy GR, Weber MJ. (1995) A proline-rich sequence unique to MEK1 and MEK2 is required for Raf binding and regulates MEK function. Mol Cell Biol 15:5214–5225

    PubMed  CAS  Google Scholar 

  • Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B, Wright A, Vanderbilt C, Cobb MH (2001) MAP kinases. Chem Rev 101:2449–2476

    Article  PubMed  CAS  Google Scholar 

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  PubMed  CAS  Google Scholar 

  • Davies SP, Reddy H, Caivano M, Cohen P (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 351:95–105

    Article  PubMed  CAS  Google Scholar 

  • Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29:117–129

    Article  PubMed  CAS  Google Scholar 

  • Downward J (2003) Targeting ras signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22

    Article  PubMed  CAS  Google Scholar 

  • Downward J (2006) Signatures guide drug choice. Nature 439:274–275

    Article  PubMed  CAS  Google Scholar 

  • Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 92:7686–7689

    Article  PubMed  CAS  Google Scholar 

  • Farooq A, Zhou MM (2004) Structure and regulation of MAPK phosphatases. Cell Signal 16:769–779.

    Article  PubMed  CAS  Google Scholar 

  • Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273:18623–18632

    Article  PubMed  CAS  Google Scholar 

  • Frost JA, Steen H, Shapiro P, Lewis T, Ahn N, Shaw PE, Cobb MH (1997) Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. EMBO J 16:6426–6438

    Article  PubMed  CAS  Google Scholar 

  • Fukuda M, Gotoh Y, Nishida E (1997) Interaction of MAP kinase with MAP kinase kinase:its possible role in the control of nucleocytoplasmic transport of MAP kinase. EMBO J 16:1901–1908

    Article  PubMed  CAS  Google Scholar 

  • Gopalbhai K, Jansen G, Beauregard G, Whiteway M, Dumas F, Wu C, Meloche S (2003) Negative regulation of MAPKK by phosphorylation of a conserved serine residue equivalent to Ser212 of MEK1. J Biol Chem 278:8118–8125

    Article  PubMed  CAS  Google Scholar 

  • Hagemann C and Rapp UR (1999) Isotype-specific functions of Raf kinases. Exp Cell Res 253:34–46

    Article  PubMed  CAS  Google Scholar 

  • Hanks SK and Quinn AM (1991) Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol 200:38–62

    PubMed  CAS  Google Scholar 

  • Haystead TA, Dent P, Wu J, Haystead CM, Sturgill TW (1992) Ordered phosphorylation of p42mapk by MAP kinase kinase. FEBS Lett 306:17–22

    Article  PubMed  CAS  Google Scholar 

  • Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-I S, Wada H, Fujimoto J, Kohno M (1999) Constitutive activation of the 41-/43-Da mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18:813–822

    Article  PubMed  CAS  Google Scholar 

  • Iacovelli L, Capobianco L, Salvatore L, Sallese M, D’Ancona GM, DeBlasi A (2001) Thyrotropin activates mitogen-activated protein kinase pathway in FRTL-5 by a cAMP-dependent protein kinase A-independent mechanism. Mol Pharmacol 60:924–933

    PubMed  CAS  Google Scholar 

  • Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA (2003) High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63:1454–1457

    PubMed  CAS  Google Scholar 

  • Kolch W (2005) Coordinating ERK/MAPK signaling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6:827–837

    Article  PubMed  CAS  Google Scholar 

  • Lackey K, Cory M, Davis R, Frye SV, Harris PA, Hunter RN, Jung DK, McDonald OB, McNutt RW, Peel MR, Rutkowske RD, Veal JM, Wood ER (2000) The discovery of potent cRaf1 kinase inhibitors. Bioorg Med Chem Lett 10:223–226

    Article  PubMed  CAS  Google Scholar 

  • Lavoie JN, L’Allemain G, Brunet A, Muller R, Pouyssegur J (1996) Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem 271:20608–20616

    Article  PubMed  CAS  Google Scholar 

  • LoRusso PM, Adjei, AA, Varterasian M, Gadgeel S, Reid J, Mitchell DY, Hanson L, deLuca P, Bruzek L, Piens J, Asbury P, VanBecelaere K, Herrera R, Sebolt-Leopold JS, Meyer MB (2005) Phase 1 and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 23:5281–5293

    Article  PubMed  CAS  Google Scholar 

  • LoRusso PM, Krishnamurthi S, Rinehart JR, Nabell L, Croghan G, Varterasian M, Sadis S, Menon SS, Leopold J, Spear MA, Meyer MB (2005) A phase 1-2 clinical study of a second generation oral MEK inhibitor, PD0325901 in patients with advanced cancer. Proc Am Soc Clin Oncol 24:Abst 3011

    Google Scholar 

  • Maloney A and Workman P (2002) HSP90 as a new therapeutic target for cancer therapy:the story unfolds. Expert Opin Biol Ther 2:3–24

    Article  PubMed  CAS  Google Scholar 

  • Marais R, Light Y, Paterson HF, Mason CS, Marshall CJ (1997) Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases. J Biol Chem 272:4378–4383

    Article  PubMed  CAS  Google Scholar 

  • Mercer KE and Pritchard CA (2003) Raf proteins and cancer:B-Raf is identified as a mutational target. Biochim Biophys Acta 1653:25–40

    PubMed  CAS  Google Scholar 

  • Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, Yan C, McConnell P, Spessard C, Banotai C, Mueller WT, Delaney A, Omer C, Sebolt-Leopold J, Dudley DT, Leung IK, Flamme C, Warmus J, Kaufman M, Barrett S, Tecle H, Hasemann CA (2004) Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 11:1192–1197

    Article  PubMed  CAS  Google Scholar 

  • Papin C, Denouel A, Calothy G, Eychene A (1996) Identification of signalling proteins interacting with B-Raf in the yeast two-hybrid system. Oncogene 12:2213–2221

    PubMed  CAS  Google Scholar 

  • Pollock PM and Meltzer PS (2002) A genome-based strategy uncovers frequent BRAF mutations in melanoma. Cancer Cell 2:5–7

    Article  PubMed  CAS  Google Scholar 

  • Pruitt K, Der CJ (2001) Ras and Rho regulation of the cell cycle and oncogenesis. Cancer Lett. 171:1–10

    Article  PubMed  CAS  Google Scholar 

  • Rinehart J, Adjei AA, LoRusso PM, Waterhouse D, Hecht JR, Natale RB, Hamid O, Varterasian M, Asbury P, Kaldjian EP, Gulyas S, Mitchell DY, Herrera R, Sebolt-Leopold JS, Meyer MB (2004) Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol 22:4456–4462

    Article  PubMed  CAS  Google Scholar 

  • Satyamoorthy K, Li G, Gerrero MR, Brose MS, Volpe P, Weber BL, VanBelle P, Elder DE, Herlyn M (2003) Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 63:756–759

    PubMed  CAS  Google Scholar 

  • Schaeffer HJ, Catling AD, Eglen ST, Collier LS, Krauss A, Weber MJ (1998) MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science 281:1668–1671

    Article  PubMed  CAS  Google Scholar 

  • Sebolt-Leopold JS (2004) MEK inhibitors:a therapeutic approach to targeting the Ras-MAP kinase pathway in tumors. Curr Pharm Design 10:1907–1914

    Article  CAS  Google Scholar 

  • Sebolt-Leopold JS and Herrera R (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4:937–947

    Article  PubMed  CAS  Google Scholar 

  • Sebolt-Leopold JS and English JM (2006) Mechanisms of drug inhibition of signaling molecules. Nature, 441:457–462.

    Article  PubMed  CAS  Google Scholar 

  • Sebolt-Leopold JS, Dudley DT, Herrera R, Van Becelaere K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski S, Leopold WR, Saltiel AR (1999) Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature 5:810–816.

    Article  CAS  Google Scholar 

  • Seger R, Ahn NG, Posada J, Munar ES, Jensen AM, Cooper JA, Cobb MH, Krebs EG (1992) Purification and characterization of mitogen-activated protein kinase activator(s) from epidermal growth factor-stimulated A431 cells. J Biol Chem 267:14373–14381

    PubMed  CAS  Google Scholar 

  • Shelton JG, Moye PW, Steelman LS, Blalock WL, Lee JT, Franklin RA, McMahon M, McCubrey JA (2003) Differential effects of kinase cascade inhibitors on neoplastic and cytokine-mediated cell proliferation. Leukemia 17:1765–1782

    Article  PubMed  CAS  Google Scholar 

  • Shimamura A, Ballif BA, Richards SA, Blenis J (2000) Rsk1 mediates a MEK-MAP kinase cell survival signal. Curr. Biol. 10:127–135

    Article  PubMed  CAS  Google Scholar 

  • Singer G, Oldt RIII, Cohen Y, Wang BG, Sidransky D, Kurman RJ, Shih IeM (2003) Mutations in BRAF and KRAS characterize the development of lowgrade ovarian serous carcinoma. J Natl Cancer Inst 95:484–486

    Article  PubMed  CAS  Google Scholar 

  • Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, Golub TR, Sebolt-Leopold J, Sellers WR, Rosen N (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439:358–362

    Article  PubMed  CAS  Google Scholar 

  • Sridhar SS, Hedley D, Siu LL (2005) Raf kinase as a target for anticancer therapeutics. Mol Cancer Ther 4:677–685

    Article  PubMed  CAS  Google Scholar 

  • Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA (2004) JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 18:189–218

    Article  PubMed  CAS  Google Scholar 

  • Takekawa M, Tatebayashi K, Saito H (2005) Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. Mol Cell 18:295–306

    Article  PubMed  CAS  Google Scholar 

  • Thompson N and Lyons J (2005) Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery. Curr Opin Pharm 5:350–356

    Article  CAS  Google Scholar 

  • Wallace EM, Lyssikatos JP, Yeh T, Winkler JD, Koch K (2005) Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. Curr Top Med Chem 5:215–229

    Article  PubMed  CAS  Google Scholar 

  • Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R, Cancer Genome Project (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867

    Article  PubMed  CAS  Google Scholar 

  • Wellbrock C, Karasarides M, Marais R (2004) The Raf proteins take centre stage. Nat Rev Mol Cell Biol 5:875–885

    Article  PubMed  CAS  Google Scholar 

  • Wilhelm SM, Carter C, Tang LY, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109

    Article  PubMed  CAS  Google Scholar 

  • Zheng CF and Guan KL (1993) Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J Biol Chem 268:23933–23939

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA

    Judith S. Sebolt-Leopold PhD, Roman Herrera PhD & Jeffrey F. Ohren PhD

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  1. Judith S. Sebolt-Leopold PhD
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  2. Roman Herrera PhD
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  3. Jeffrey F. Ohren PhD
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Editors and Affiliations

  1. Georg-Speyer-Haus, Institute for Biomedical Research, Paul-Ehrlich-Str. 42-44, 60596, Frankfurt am Main, Germany

    Bernd Groner (Director) (Director)

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Sebolt-Leopold, J.S., Herrera, R., Ohren, J.F. (2007). The Mitogen-Activated Protein Kinase Pathway for Molecular-Targeted Cancer Treatment. In: Groner, B. (eds) Targeted Interference with Signal Transduction Events. Resent Results in Cancer Research, vol 172. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-31209-3_9

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  • DOI: https://doi.org/10.1007/978-3-540-31209-3_9

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