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Minor-Driver Mutant

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Molecular Targeted Therapy of Lung Cancer

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Abstract

Representative driver oncogenes such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, and B-rapidly accelerated fibrosarcoma (BRAF) have recently been identified as new genetic aberrations in patients with non-small cell lung cancer (NSCLC). Additionally, rearranged during transfection (RET) and c-ros oncogene 1 (ROS1) fusion genes, which are minor-driver oncogenes, are each found in 1–2 % of NSCLC and represent distinct molecular subsets. Studies based on preclinical and clinical studies of several fusion-positive patients indicate that inhibiting the kinase activity of the RET and ROS1 fusion proteins is a promising therapeutic strategy. Therefore, there are several ongoing clinical trials aimed at examining the efficacy of tyrosine kinase inhibitors (TKIs) against fusion proteins in patients with fusion-positive NSCLC. Other minor gene mutations (HER2/ERBB2, NTRK1, NRG1, FGFR1/FGFR3, DDR2, and PIK3CA) that are targetable by existing TKIs have also been identified in patients with NSCLCs. It is necessary to establish systematic genomic testing algorithms to identify defined subsets of patients with NSCLC for whom effective drug therapies are available either commercially or through clinical trials.

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References

  1. Ohe Y, Ohashi Y, Kubota K et al (2007) Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 18:317–323

    Article  CAS  PubMed  Google Scholar 

  2. Maemondo M, Inoue A, Kobayashi K et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388

    Article  CAS  PubMed  Google Scholar 

  3. Shaw AT, Kim DW, Nakagawa K et al (2013) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385–2394

    Article  CAS  PubMed  Google Scholar 

  4. Mok TS, Wu YL, Thongprasert S et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957

    Article  CAS  PubMed  Google Scholar 

  5. Kohno T, Ichikawa H, Totoki Y et al (2012) KIF5B-RET fusions in lung adenocarcinoma. Nat Med 18:375–377

    Article  CAS  PubMed  Google Scholar 

  6. Takeuchi K, Soda M, Togashi Y et al (2012) RET, ROS1 and ALK fusions in lung cancer. Nat Med 18:378–381

    Article  CAS  PubMed  Google Scholar 

  7. Drilon A, Wang L, Hasanovic A et al (2013) Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov 3:630–635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wu YM, Su F, Kalyana-Sundaram S et al (2013) Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 3:636–647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cancer Genome Atlas Research Network (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519–525

    Article  Google Scholar 

  10. Koivunen JP, Mermel C, Zejnullahu K et al (2008) EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 14:4275–4283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bergethon K, Shaw AT, Ou SH et al (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30:863–870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pao W, Hutchinson KE (2012) Chipping away at the lung cancer genome. Nat Med 18:349–351

    Article  CAS  PubMed  Google Scholar 

  13. Li T, Kung HJ, Mack PC, Gandara DR (2013) Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol 31:1039–1049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kohno T, Tsuta K, Tsuchihara K et al (2013) RET fusion gene: translation to personalized lung cancer therapy. Cancer Sci 104:1396–1400

    Article  CAS  PubMed  Google Scholar 

  15. Kris MG, Johnson BE, Berry LD et al (2014) Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:1998–2006

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lopez-Chavez A, Thomas A, Rajan A et al (2015) Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol 33:1000–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Eng C (1999) RET proto-oncogene in the development of human cancer. J Clin Oncol 17:380–393

    CAS  PubMed  Google Scholar 

  18. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355–365

    Article  CAS  PubMed  Google Scholar 

  19. Plaza-Menacho I, Mologni L, McDonald NQ (2014) Mechanisms of RET signaling in cancer: current and future implications for targeted therapy. Cell Signal 26:1743–1752

    Article  CAS  PubMed  Google Scholar 

  20. Lipson D, Capelletti M, Yelensky R et al (2012) Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 18:382–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tsuta K, Kohno T, Yoshida A et al (2014) RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis. Br J Cancer 110:1571–1578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Matsubara D, Kanai Y, Ishikawa S et al (2012) Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad. J Thorac Oncol 7:1872–1876

    Article  CAS  PubMed  Google Scholar 

  23. Chao BH, Briesewitz R, Villalona-Calero MA (2012) RET fusion genes in non-small-cell lung cancer. J Clin Oncol 30:4439–4441

    Article  CAS  PubMed  Google Scholar 

  24. Gautschi O, Zander T, Keller FA et al (2013) A patient with lung adenocarcinoma and RET fusion treated with vandetanib. J Thorac Oncol 8:e43–e44

    Article  PubMed  Google Scholar 

  25. Falchook GS, Ordonez NG, Bastida CC et al (2016) Effect of the RET inhibitor vandetanib in a patient with RET fusion-positive metastatic non-small-cell lung cancer. J Clin Oncol 34:e141–e144

    Article  PubMed  Google Scholar 

  26. Wu H, Shih JY, Yang JC (2015) Rapid response to sunitinib in a patient with lung adenocarcinoma harboring KIF5B-RET fusion gene. J Thorac Oncol 10:e95–e96

    Article  PubMed  Google Scholar 

  27. Yoh K, Seto T, Satouchi M et al (2016) Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial. Lancet Respir Med

    Google Scholar 

  28. Drilon A, Rekhtman N, Arcila M et al (2016) Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an openlabel, single-centre, phase 2, single-arm trial. Lancet Oncol

    Google Scholar 

  29. Robinson DR, Wu YM, Lin SF (2000) The protein tyrosine kinase family of the human genome. Oncogene 19:5548–5557

    Article  CAS  PubMed  Google Scholar 

  30. Chin LP, Soo RA, Soong R, Ou SH (2012) Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer. J Thorac Oncol 7:1625–1630

    Article  CAS  PubMed  Google Scholar 

  31. Davies KD, Le AT, Theodoro MF et al (2012) Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin Cancer Res 18:4570–4579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ou SH, Bartlett CH, Mino-Kenudson M et al (2012) Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist 17:1351–1375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sholl LM, Sun H, Butaney M et al (2013) ROS1 immunohistochemistry for detection of ROS1-rearranged lung adenocarcinomas. Am J Surg Pathol 37:1441–1449

    Article  PubMed  Google Scholar 

  34. Shaw AT, Ou SH, Bang YJ et al (2014) Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371:1963–1971

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mazieres J, Zalcman G, Crino L et al (2015) Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol 33:992–999

    Article  CAS  PubMed  Google Scholar 

  36. Awad MM, Katayama R, McTigue M et al (2013) Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 368:2395–2401

    Article  CAS  PubMed  Google Scholar 

  37. Davies KD, Mahale S, Astling DP et al (2013) Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer. PLoS One 8:e82236

    Article  PubMed  PubMed Central  Google Scholar 

  38. Davare MA, Saborowski A, Eide CA et al (2013) Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Proc Natl Acad Sci U S A 110:19519–19524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310

    Article  CAS  PubMed  Google Scholar 

  40. Flaherty KT, Infante JR, Daud A et al (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:1694–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Davies H, Bignell GR, Cox C et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  CAS  PubMed  Google Scholar 

  42. Paik PK, Arcila ME, Fara M et al (2011) Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 29:2046–2051

    Article  PubMed  PubMed Central  Google Scholar 

  43. Cardarella S, Ogino A, Nishino M et al (2013) Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res 19:4532–4540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Marchetti A, Felicioni L, Malatesta S et al (2011) Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 29:3574–3579

    Article  CAS  PubMed  Google Scholar 

  45. McCourt CM, McArt DG, Mills K et al (2013) Validation of next generation sequencing technologies in comparison to current diagnostic gold standards for BRAF, EGFR and KRAS mutational analysis. PLoS One 8:e69604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ilie M, Long E, Hofman V et al (2013) Diagnostic value of immunohistochemistry for the detection of the BRAFV600E mutation in primary lung adenocarcinoma Caucasian patients. Ann Oncol 24:742–748

    Article  CAS  PubMed  Google Scholar 

  47. Pratilas CA, Hanrahan AJ, Halilovic E et al (2008) Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 68:9375–9383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hyman DM, Puzanov I, Subbiah V et al (2015) Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 373:726–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gautschi O, Peters S, Zoete V et al (2013) Lung adenocarcinoma with BRAF G469 L mutation refractory to vemurafenib. Lung Cancer 82:365–367

    Article  PubMed  Google Scholar 

  50. Hauschild A, Grob JJ, Demidov LV et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358–365

    Article  CAS  PubMed  Google Scholar 

  51. Falchook GS, Long GV, Kurzrock R et al (2012) Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379:1893–1901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sullivan RJ, Flaherty KT (2013) Resistance to BRAF-targeted therapy in melanoma. Eur J Cancer 49:1297–1304

    Article  CAS  PubMed  Google Scholar 

  53. Lito P, Pratilas CA, Joseph EW et al (2012) Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22:668–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rudin CM, Hong K, Streit M (2013) Molecular characterization of acquired resistance to the BRAF inhibitor dabrafenib in a patient with BRAF-mutant non-small-cell lung cancer. J Thorac Oncol 8:e41–e42

    Article  PubMed  PubMed Central  Google Scholar 

  55. Mazieres J, Peters S, Lepage B et al (2013) Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 31:1997–2003

    Article  CAS  PubMed  Google Scholar 

  56. Heinmoller P, Gross C, Beyser K et al (2003) HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin. Clin Cancer Res 9:5238–5243

    PubMed  Google Scholar 

  57. Stephens P, Hunter C, Bignell G et al (2004) Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431:525–526

    Article  CAS  PubMed  Google Scholar 

  58. Perera SA, Li D, Shimamura T et al (2009) HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy. Proc Natl Acad Sci U S A 106:474–479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Shimamura T, Ji H, Minami Y et al (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 66:6487–6491

    Article  CAS  PubMed  Google Scholar 

  60. De Greve J, Teugels E, Geers C et al (2012) Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer 76:123–127

    Article  CAS  PubMed  Google Scholar 

  61. Janne PA, Ou SH, Kim DW et al (2014) Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial. Lancet Oncol 15:1433–1441

    Article  CAS  PubMed  Google Scholar 

  62. Gandhi L, Bahleda R, Tolaney SM et al (2014) Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. J Clin Oncol 32:68–75

    Article  CAS  PubMed  Google Scholar 

  63. Vaishnavi A, Capelletti M, Le AT et al (2013) Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med 19:1469–1472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Farago AF, Le LP, Zheng Z et al (2015) Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer. J Thorac Oncol 10:1670–1674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fernandez-Cuesta L, Plenker D, Osada H et al (2014) CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 4:415–422

    Article  CAS  PubMed  Google Scholar 

  66. Nakaoku T, Tsuta K, Ichikawa H et al (2014) Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res 20:3087–3093

    Article  CAS  PubMed  Google Scholar 

  67. Dutt A, Ramos AH, Hammerman PS et al (2011) Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One 6:e20351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Weiss J, Sos ML, Seidel D et al (2010) Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2:62ra93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cancer Genome Atlas Research Network (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543–550

    Article  Google Scholar 

  70. Capelletti M, Dodge ME, Ercan D et al (2014) Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma. Clin Cancer Res 20:6551–6558

    Article  CAS  PubMed  Google Scholar 

  71. Majewski IJ, Mittempergher L, Davidson NM et al (2013) Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing. J Pathol 230:270–276

    Article  CAS  PubMed  Google Scholar 

  72. Helsten T, Elkin S, Arthur E et al (2016) The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res 22:259–267

    Article  CAS  PubMed  Google Scholar 

  73. Hammerman PS, Sos ML, Ramos AH et al (2011) Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov 1:78–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bai Y, Kim JY, Watters JM et al (2014) Adaptive responses to dasatinib-treated lung squamous cell cancer cells harboring DDR2 mutations. Cancer Res 74:7217–7228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sun Y, Ren Y, Fang Z et al (2010) Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. J Clin Oncol 28:4616–4620

    Article  PubMed  PubMed Central  Google Scholar 

  76. Kawano O, Sasaki H, Endo K et al (2006) PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer 54:209–215

    Article  PubMed  Google Scholar 

  77. Sequist LV, Waltman BA, Dias-Santagata D et al (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3:75ra26

    Article  PubMed  PubMed Central  Google Scholar 

  78. Engelman JA, Mukohara T, Zejnullahu K et al (2006) Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest 116:2695–2706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Engelman JA, Chen L, Tan X et al (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan

    Akihiko Miyanaga

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Correspondence to Akihiko Miyanaga .

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  1. Department of Medical Oncology Graduate School of Medicine, Chiba University, Chiba, Japan

    Yuichi Takiguchi

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Miyanaga, A. (2017). Minor-Driver Mutant. In: Takiguchi, Y. (eds) Molecular Targeted Therapy of Lung Cancer. Springer, Singapore. https://doi.org/10.1007/978-981-10-2002-5_12

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