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Lung Cancer Genomics in the Era of Accelerated Targeted Drug Development

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Lung Cancer and Personalized Medicine: Novel Therapies and Clinical Management

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 890))

Abstract

Lung cancer is the leading cause of cancer-related deaths in the United States and the 5-year overall survival outlook for a patient has not improved in several decades. Recently, however, molecular and genomic profiling of the lung tumors has revealed recurring somatic mutations. As a result the therapeutic landscape of lung cancer is undergoing a paradigm shift from a purely histology-based understanding of the disease to subtype distinctions based on tumor genetics, which has launched cancer-specific, mechanism-based targeted therapies with clear benefit to patients. While targeted therapy advancements are being made at an ever increasing rate, a new challenge in the form of drug resistance has also emerged. This review summarizes the current literature for these issues.

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References

  1. Sharma SV, Settleman J (2007) Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev 21:3214–3231

    Article  PubMed  CAS  Google Scholar 

  2. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr et al (2013) Cancer genome landscapes. Science 339:1546–1558

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519–525

    Google Scholar 

  4. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  PubMed  CAS  Google Scholar 

  5. Beltran AS, Blancafort P (2011) Reactivation of MASPIN in non-small cell lung carcinoma (NSCLC) cells by artificial transcription factors (ATFs). Epigenetics 6:224–235

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Lee SH, Park BJ (2011) p53 activation by blocking Snail: a novel pharmacological strategy for cancer. Curr Pharm Des 17:610–617

    Article  PubMed  CAS  Google Scholar 

  7. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Article  PubMed  CAS  Google Scholar 

  8. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139

    Article  PubMed  CAS  Google Scholar 

  9. Pao W, Miller V, Zakowski M, Doherty J, Politi K et al (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306–13311

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Pao W, Girard N (2011) New driver mutations in non-small-cell lung cancer. Lancet Oncol 12:175–180

    Article  PubMed  CAS  Google Scholar 

  11. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566

    Article  PubMed  CAS  Google Scholar 

  12. (2013) A genomics-based classification of human lung tumors. Sci Transl Med 5:209ra153

    Google Scholar 

  13. Howlander N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Rulhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK (2011) SEER cancer statistics review, 1975-2008. National Cancer Institute, Bethesda

    Google Scholar 

  14. Pao W, Iafrate AJ, Su Z (2011) Genetically informed lung cancer medicine. J Pathol 223:230–240

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  16. Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ et al (2012) Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150:1107–1120

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D et al (2010) Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466:869–873

    Article  PubMed  CAS  Google Scholar 

  18. Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B et al (2002) Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 62:3659–3662

    PubMed  CAS  Google Scholar 

  19. Huang S, Benavente S, Armstrong EA, Li C, Wheeler DL et al (2011) p53 modulates acquired resistance to EGFR inhibitors and radiation. Cancer Res 71:7071–7079

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A (2001) The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer 8:11–31

    Article  PubMed  CAS  Google Scholar 

  21. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V et al (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132

    Article  PubMed  CAS  Google Scholar 

  22. Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H et al (2007) Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11:217–227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H et al (2008) The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 105:2070–2075

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Tam IY, Chung LP, Suen WS, Wang E, Wong MC et al (2006) Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res 12:1647–1653

    Article  PubMed  CAS  Google Scholar 

  25. Yamamoto H, Toyooka S, Mitsudomi T (2009) Impact of EGFR mutation analysis in non-small cell lung cancer. Lung Cancer 63:315–321

    Article  PubMed  Google Scholar 

  26. Hirsch FR, Janne PA, Eberhardt WE, Cappuzzo F, Thatcher N et al (2013) Epidermal growth factor receptor inhibition in lung cancer: status 2012. J Thorac Oncol 8:373–384

    PubMed  CAS  Google Scholar 

  27. Cardarella S, Johnson BE (2013) The impact of genomic changes on treatment of lung cancer. Am J Respir Crit Care Med 188:770–775

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Balak MN, Gong Y, Riely GJ, Somwar R, Li AR et al (2006) Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12:6494–6501

    Article  PubMed  CAS  Google Scholar 

  29. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M et al (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339–346

    Article  PubMed  CAS  Google Scholar 

  30. Eberhard DA, Giaccone G, Johnson BE (2008) Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. J Clin Oncol 26:983–994

    Article  PubMed  Google Scholar 

  31. Russell PA, Barnett SA, Walkiewicz M, Wainer Z, Conron M et al (2013) Correlation of mutation status and survival with predominant histologic subtype according to the new IASLC/ATS/ERS lung adenocarcinoma classification in stage III (N2) patients. J Thorac Oncol 8:461–468

    Article  PubMed  Google Scholar 

  32. Bauml J, Mick R, Zhang Y, Watt CD, Vachani A et al (2013) Frequency of EGFR and KRAS mutations in patients with non small cell lung cancer by racial background: do disparities exist? Lung Cancer 81:347–353

    Article  PubMed  PubMed Central  Google Scholar 

  33. Yang SH, Mechanic LE, Yang P, Landi MT, Bowman ED et al (2005) Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 11:2106–2110

    Article  PubMed  CAS  Google Scholar 

  34. Reinersman JM, Johnson ML, Riely GJ, Chitale DA, Nicastri AD et al (2011) Frequency of EGFR and KRAS mutations in lung adenocarcinomas in African Americans. J Thorac Oncol 6:28–31

    Article  PubMed  PubMed Central  Google Scholar 

  35. Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R et al (2009) PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69:3256–3261

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T et al (2004) Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 64:8919–8923

    Article  PubMed  CAS  Google Scholar 

  37. Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K et al (2005) The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res 11:1167–1173

    PubMed  CAS  Google Scholar 

  38. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD et al (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Rekhtman N, Paik PK, Arcila ME, Tafe LJ, Oxnard GR et al (2012) Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res 18:1167–1176

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Ohtsuka K, Ohnishi H, Fujiwara M, Kishino T, Matsushima S et al (2007) Abnormalities of epidermal growth factor receptor in lung squamous-cell carcinomas, adenosquamous carcinomas, and large-cell carcinomas: tyrosine kinase domain mutations are not rare in tumors with an adenocarcinoma component. Cancer 109:741–750

    Article  PubMed  CAS  Google Scholar 

  41. Karnoub AE, Weinberg RA (2008) Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9:517–531

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  43. Rodenhuis S, Slebos RJ (1992) Clinical significance of ras oncogene activation in human lung cancer. Cancer Res 52:2665s–2669s

    Google Scholar 

  44. Sequist LV, Heist RS, Shaw AT, Fidias P, Rosovsky R et al (2011) Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol 22:2616–2624

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Riely GJ, Kris MG, Rosenbaum D, Marks J, Li A et al (2008) Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 14:5731–5734

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Linardou H, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D et al (2008) Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 9:962–972

    Article  PubMed  CAS  Google Scholar 

  47. Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J et al (2013) Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14:38–47

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  49. Brose MS, Volpe P, Feldman M, Kumar M, Rishi I et al (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62:6997–7000

    PubMed  CAS  Google Scholar 

  50. Paik PK, Arcila ME, Fara M, Sima CS, Miller VA 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 

  51. Gautschi O, Pauli C, Strobel K, Hirschmann A, Printzen G et al (2012) A patient with BRAF V600E lung adenocarcinoma responding to vemurafenib. J Thorac Oncol 7:e23–e24

    Article  PubMed  Google Scholar 

  52. Hirsch FR, Varella-Garcia M, Franklin WA, Veve R, Chen L et al (2002) Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br J Cancer 86:1449–1456

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M et al (2005) Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 65:1642–1646

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  55. Clamon G, Herndon J, Kern J, Govindan R, Garst J et al (2005) Lack of trastuzumab activity in nonsmall cell lung carcinoma with overexpression of erb-B2: 39810: a phase II trial of Cancer and Leukemia Group B. Cancer 103:1670–1675

    Article  PubMed  CAS  Google Scholar 

  56. Gatzemeier U, Groth G, Butts C, Van Zandwijk N, Shepherd F et al (2004) Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol 15:19–27

    Article  PubMed  CAS  Google Scholar 

  57. Kelly RJ, Carter CA, Giaccone G (2012) HER2 mutations in non-small-cell lung cancer can be continually targeted. J Clin Oncol 30:3318–3319

    Article  PubMed  Google Scholar 

  58. De Greve J, Teugels E, Geers C, Decoster L, Galdermans D 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  PubMed  Google Scholar 

  59. Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D et al (2011) Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 29:909–916

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Sadiq AA, Salgia R (2013) MET as a possible target for non-small-cell lung cancer. J Clin Oncol 31:1089–1096

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Cappuzzo F, Marchetti A, Skokan M, Rossi E, Gajapathy S et al (2009) Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 27:1667–1674

    Article  PubMed  PubMed Central  Google Scholar 

  62. Toschi L, Cappuzzo F (2010) Clinical implications of MET gene copy number in lung cancer. Future Oncol 6:239–247

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  64. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF et al (2013) Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 19:2240–2247

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043

    Article  PubMed  CAS  Google Scholar 

  66. Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt JH Jr et al (2013) Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 31:4105–4114

    Article  PubMed  CAS  Google Scholar 

  67. Spigel DR, Edelman MJ, Mok T, O’Byrne K, Paz-Ares L et al (2012) Treatment Rationale Study Design for the MetLung Trial: a randomized, double-blind phase III study of onartuzumab (MetMAb) in combination with erlotinib versus erlotinib alone in patients who have received standard chemotherapy for stage IIIB or IV met-positive non-small-cell lung cancer. Clin Lung Cancer 13:500–504

    Article  PubMed  CAS  Google Scholar 

  68. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y et al (2011) Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10:2298–2308

    Article  PubMed  CAS  Google Scholar 

  69. Cui JJ, Tran-Dube M, Shen H, Nambu M, Kung PP et al (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 54:6342–6363

    Article  PubMed  CAS  Google Scholar 

  70. Burgess TL, Sun J, Meyer S, Tsuruda TS, Elliott G et al (2010) Biochemical characterization of AMG 102: a neutralizing, fully human monoclonal antibody to human and nonhuman primate hepatocyte growth factor. Mol Cancer Ther 9:400–409

    Article  PubMed  CAS  Google Scholar 

  71. Gordon MS, Sweeney CS, Mendelson DS, Eckhardt SG, Anderson A et al (2010) Safety, pharmacokinetics, and pharmacodynamics of AMG 102, a fully human hepatocyte growth factor-neutralizing monoclonal antibody, in a first-in-human study of patients with advanced solid tumors. Clin Cancer Res 16:699–710

    Article  PubMed  CAS  Google Scholar 

  72. Beau-Faller M, Ruppert AM, Voegeli AC, Neuville A, Meyer N et al (2008) MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naive cohort. J Thorac Oncol 3:331–339

    Article  PubMed  Google Scholar 

  73. Drilon A, Rekhtman N, Ladanyi M, Paik P (2012) Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol 13:e418–e426

    Article  PubMed  CAS  Google Scholar 

  74. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ et al (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184–2191

    Article  PubMed  CAS  Google Scholar 

  75. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551

    Article  PubMed  CAS  Google Scholar 

  76. Wistuba II, Behrens C, Virmani AK, Mele G, Milchgrub S et al (2000) High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res 60:1949–1960

    PubMed  CAS  Google Scholar 

  77. Wistuba II, Behrens C, Milchgrub S, Bryant D, Hung J et al (1999) Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma. Oncogene 18:643–650

    Article  PubMed  CAS  Google Scholar 

  78. Zheng CX, Gu ZH, Han B, Zhang RX, Pan CM et al (2013) Whole-exome sequencing to identify novel somatic mutations in squamous cell lung cancers. Int J Oncol 43:755–764

    PubMed  CAS  Google Scholar 

  79. Roth BJ, Krilov L, Adams S, Aghajanian CA, Bach P et al (2013) Clinical cancer advances 2012: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 31:131–161

    Article  PubMed  Google Scholar 

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

    Google Scholar 

  81. Perez-Moreno P, Brambilla E, Thomas R, Soria JC (2012) Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities. Clin Cancer Res 18:2443–2451

    Article  PubMed  CAS  Google Scholar 

  82. Kim CH (2013) Druggable targets of squamous cell lung cancer. Tuberc Respir Dis (Seoul) 75:231–235

    Article  Google Scholar 

  83. Go H, Jeon YK, Park HJ, Sung SW, Seo JW et al (2010) High MET gene copy number leads to shorter survival in patients with non-small cell lung cancer. J Thorac Oncol 5:305–313

    Article  PubMed  Google Scholar 

  84. Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S et al (2009) SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 41:1238–1242

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Hussenet T, du Manoir S (2010) SOX2 in squamous cell carcinoma: amplifying a pleiotropic oncogene along carcinogenesis. Cell Cycle 9:1480–1486

    Article  PubMed  CAS  Google Scholar 

  86. Hussenet T, Dali S, Exinger J, Monga B, Jost B et al (2010) SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung squamous cell carcinomas. PLoS One 5, e8960

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Ramos AH, Dutt A, Mermel C, Perner S, Cho J et al (2009) Amplification of chromosomal segment 4q12 in non-small cell lung cancer. Cancer Biol Ther 8:2042–2050

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Rooney M, Devarakonda S, Govindan R (2013) Genomics of squamous cell lung cancer. Oncologist 18:707–716

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Grob TJ, Kannengiesser I, Tsourlakis MC, Atanackovic D, Koenig AM et al (2012) Heterogeneity of ERBB2 amplification in adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma of the lung. Mod Pathol 25:1566–1573

    Article  PubMed  CAS  Google Scholar 

  90. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL et al (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439–444

    Article  PubMed  CAS  Google Scholar 

  91. Malanga D, Scrima M, De Marco C, Fabiani F, De Rosa N et al (2008) Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung. Cell Cycle 7:665–669

    Article  PubMed  CAS  Google Scholar 

  92. Heist RS, Sequist LV, Engelman JA (2012) Genetic changes in squamous cell lung cancer: a review. J Thorac Oncol 7:924–933

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G et al (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439:358–362

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Day E, Waters B, Spiegel K, Alnadaf T, Manley PW et al (2008) Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. Eur J Pharmacol 599:44–53

    Article  PubMed  CAS  Google Scholar 

  95. Hammerman PS, Sos ML, Ramos AH, Xu C, Dutt A 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  PubMed  PubMed Central  CAS  Google Scholar 

  96. Yamamoto H, Shigematsu H, Nomura M, Lockwood WW, Sato M et al (2008) PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 68:6913–6921

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Samuels Y, Diaz LA Jr, Schmidt-Kittler O, Cummins JM, Delong L et al (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7:561–573

    Article  PubMed  CAS  Google Scholar 

  98. Shames DS, Wistuba II (2014) The evolving genomic classification of lung cancer. J Pathol 232:121–133

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Thomas A, Rajan A, Lopez-Chavez A, Wang Y, Giaccone G (2013) From targets to targeted therapies and molecular profiling in non-small cell lung carcinoma. Ann Oncol 24:577–585

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Popovic R, Licht JD (2012) Emerging epigenetic targets and therapies in cancer medicine. Cancer Discov 2:405–413

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Zagni C, Chiacchio U, Rescifina A (2013) Histone methyltransferase inhibitors: novel epigenetic agents for cancer treatment. Curr Med Chem 20:167–185

    Article  PubMed  CAS  Google Scholar 

  102. Jin G, Kim MJ, Jeon HS, Choi JE, Kim DS et al (2010) PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers. Lung Cancer 69:279–283

    Article  PubMed  Google Scholar 

  103. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  PubMed  CAS  Google Scholar 

  104. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. van Meerbeeck JP, Fennell DA, De Ruysscher DK (2011) Small-cell lung cancer. Lancet 378:1741–1755

    Article  PubMed  Google Scholar 

  106. Chute JP, Chen T, Feigal E, Simon R, Johnson BE (1999) Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol 17:1794–1801

    PubMed  CAS  Google Scholar 

  107. Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z et al (2012) Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 44:1111–1116

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D et al (2012) Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 44:1104–1110

    Article  PubMed  CAS  Google Scholar 

  109. Iwakawa R, Takenaka M, Kohno T, Shimada Y, Totoki Y et al (2013) Genome-wide identification of genes with amplification and/or fusion in small cell lung cancer. Genes Chromosomes Cancer 52:802–816

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Kim YH, Girard L, Giacomini CP, Wang P, Hernandez-Boussard T et al (2006) Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification. Oncogene 25:130–138

    Article  PubMed  CAS  Google Scholar 

  111. Wistuba II, Gazdar AF, Minna JD (2001) Molecular genetics of small cell lung carcinoma. Semin Oncol 28:3–13

    Article  PubMed  CAS  Google Scholar 

  112. Larsen JE, Minna JD (2011) Molecular biology of lung cancer: clinical implications. Clin Chest Med 32:703–740

    Article  PubMed  PubMed Central  Google Scholar 

  113. Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ et al (2008) Modelling Myc inhibition as a cancer therapy. Nature 455:679–683

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J et al (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904–917

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Sos ML, Dietlein F, Peifer M, Schottle J, Balke-Want H et al (2012) A framework for identification of actionable cancer genome dependencies in small cell lung cancer. Proc Natl Acad Sci U S A 109:17034–17039

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693–1703

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB et al (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247–4253

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Rikova K, Guo A, Zeng Q, Possemato A, Yu J et al (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131:1190–1203

    Article  PubMed  CAS  Google Scholar 

  119. Gainor JF, Shaw AT (2013) Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 18:865–875

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Shaw AT, Hsu PP, Awad MM, Engelman JA (2013) Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer 13:772–787

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  124. Seo JS, Ju YS, Lee WC, Shin JY, Lee JK et al (2012) The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 22:2109–2119

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Sasaki T, Rodig SJ, Chirieac LR, Janne PA (2010) The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 46:1773–1780

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S et al (2009) KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 15:3143–3149

    Article  PubMed  CAS  Google Scholar 

  128. Fang DD, Zhang B, Gu Q, Lira M, Xu Q et al (2014) HIP1-ALK, a novel ALK fusion variant that responds to crizotinib. J Thorac Oncol 9:285–294

    Article  PubMed  CAS  Google Scholar 

  129. Togashi Y, Soda M, Sakata S, Sugawara E, Hatano S et al (2012) KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One 7, e31323

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Choi YL, Lira ME, Hong M, Kim RN, Choi SJ et al (2014) A novel fusion of TPR and ALK in lung adenocarcinoma. J Thorac Oncol 9:563–566

    Article  PubMed  CAS  Google Scholar 

  131. Bray F, Ren JS, Masuyer E, Ferlay J (2013) Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer 132:1133–1145

    Article  PubMed  CAS  Google Scholar 

  132. Ferlay J, Shin HR, Bray F, Forman D, Mathers C et al (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917

    Article  PubMed  CAS  Google Scholar 

  133. Jabbour E, Cortes JE, Ghanem H, O’Brien S, Kantarjian HM (2008) Targeted therapy in chronic myeloid leukemia. Expert Rev Anticancer Ther 8:99–110

    Article  PubMed  CAS  Google Scholar 

  134. Wong DW, Leung EL, So KK, Tam IY, Sihoe AD et al (2009) The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 115:1723–1733

    Article  PubMed  CAS  Google Scholar 

  135. Ou SH (2011) Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond. Drug Des Devel Ther 5:471–485

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E et al (2014) Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370:1189–1197

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Chabner BA (2014) Approval after phase I: ceritinib runs the three-minute mile. Oncologist 19:577–578

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Yoshida A, Kohno T, Tsuta K, Wakai S, Arai Y et al (2013) ROS1-rearranged lung cancer: a clinicopathologic and molecular study of 15 surgical cases. Am J Surg Pathol 37:554–562

    Article  PubMed  Google Scholar 

  141. Rimkunas VM, Crosby KE, Li D, Hu Y, Kelly ME et al (2012) Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: identification of a FIG-ROS1 fusion. Clin Cancer Res 18:4449–4457

    Article  PubMed  CAS  Google Scholar 

  142. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND et al (2012) Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150:1121–1134

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Suehara Y, Arcila M, Wang L, Hasanovic A, Ang D et al (2012) Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions. Clin Cancer Res 18:6599–6608

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Acquaviva J, Wong R, Charest A (2009) The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer. Biochim Biophys Acta 1795:37–52

    PubMed  CAS  Google Scholar 

  145. Ju YS, Lee WC, Shin JY, Lee S, Bleazard T et al (2012) A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res 22:436–445

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Davies KD, Doebele RC (2013) Molecular pathways: ROS1 fusion proteins in cancer. Clin Cancer Res 19:4040–4045

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Suzuki M, Makinoshima H, Matsumoto S, Suzuki A, Mimaki S et al (2013) Identification of a lung adenocarcinoma cell line with CCDC6-RET fusion gene and the effect of RET inhibitors in vitro and in vivo. Cancer Sci 104:896–903

    Article  PubMed  CAS  Google Scholar 

  153. Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:823–837

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B et al (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239–246

    Article  PubMed  CAS  Google Scholar 

  155. Zhou C, Wu YL, Chen G, Feng J, Liu XQ et al (2011) Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12:735–742

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  157. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I et al (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11:121–128

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  159. Yasuda H, Kobayashi S, Costa DB (2012) EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 13:e23–e31

    Article  PubMed  CAS  Google Scholar 

  160. Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR et al (2013) Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 5:216ra177

    Google Scholar 

  161. Girard N, Lou E, Azzoli CG, Reddy R, Robson M et al (2010) Analysis of genetic variants in never-smokers with lung cancer facilitated by an Internet-based blood collection protocol: a preliminary report. Clin Cancer Res 16:755–763

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Ohashi K, Maruvka YE, Michor F, Pao W (2013) Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 31:1070–1080

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Arcila ME, Oxnard GR, Nafa K, Riely GJ, Solomon SB et al (2011) Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res 17:1169–1180

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Heuckmann JM, Holzel M, Sos ML, Heynck S, Balke-Want H et al (2011) ALK mutations conferring differential resistance to structurally diverse ALK inhibitors. Clin Cancer Res 17:7394–7401

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Sasaki T, Okuda K, Zheng W, Butrynski J, Capelletti M et al (2010) The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res 70:10038–10043

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  167. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502:333–339

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA et al (2014) Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505:495–501

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, 4100 John R, Detroit, MI, 48201, USA

    Priyanga Wijesinghe Ph.D. & Aliccia Bollig-Fischer Ph.D.

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  1. Priyanga Wijesinghe Ph.D.
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  2. Aliccia Bollig-Fischer Ph.D.
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  1. Wayne State University, Karmanos Cancer Institute, Detroit, Michigan, USA

    Aamir Ahmad

  2. Karamanos Cancer Institute, Wayne State University, Detroit, Michigan, USA

    Shirish M. Gadgeel

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Wijesinghe, P., Bollig-Fischer, A. (2016). Lung Cancer Genomics in the Era of Accelerated Targeted Drug Development. In: Ahmad, A., Gadgeel, S. (eds) Lung Cancer and Personalized Medicine: Novel Therapies and Clinical Management. Advances in Experimental Medicine and Biology, vol 890. Springer, Cham. https://doi.org/10.1007/978-3-319-24932-2_1

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