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Other signalization targets

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Abstract

Treatment decisions for patients with lung cancer have historically been based upon tumor morphological analysis. Over the past decade, some molecular alterations have been identified as being necessary and sufficient to drive tumor carcinogenesis. These “driver” mutations occur in genes that encode signaling proteins critical for cellular proliferation and survival. Epidermal growth factor (EGF) receptor (EGFR) mutations are the best illustration of the therapeutic relevance of identifying such molecular clusters of lung cancer based on driver genetic alterations that predict the efficacy of specific tyrosine kinase inhibitors, a strategy referred to as “personalized medicine.” Besides EGFR and ALK, other genes harboring driver molecular alterations have been identified as part of integrated genomic studies of lung cancers. The objectives of this review are (1) to provide the reader with preclinical and clinical data on these new oncogenic mutations, focusing on druggable ones; (2) to discuss the dynamic nature of lung cancer molecular features in the context of acquired resistance to specific inhibitors; and (3) to highlight emerging data on other cancer hallmarks that may be of interest from a therapeutic perspective in the next future. From bench to bedside, personalized medicine represents a major revolution in the treatment of lung cancer.

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References

  1. American Cancer Society (2007) Cancer facts and figures 2007. American Cancer Society, Atlanta

    Google Scholar 

  2. World Health Organization (2004) WHO histological classification of tumours of the lung. In: Travis WB, Brambilla A, Muller-Hermelinck HK, Harris CC (eds) World Health Organization classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. IARC, Lyon, p 10

    Google Scholar 

  3. Scagliotti GV, Parikh P, von Pawel 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 

  4. Sandler A, Gray R, Perry MC et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550

    Article  PubMed  CAS  Google Scholar 

  5. Cappuzzo F, Ciuleanu T, Stelmakh L et al (2006) Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11:521–529

    Article  Google Scholar 

  6. Olaussen KA, Dunant A, Fouret P et al (2006) DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355:983–991

    Article  PubMed  CAS  Google Scholar 

  7. Weir BA, Woo MS, Getz G et al (2007) Characterizing the cancer genome in lung adenocarcinoma. Nature 450:893–898

    Article  PubMed  CAS  Google Scholar 

  8. Motoi N, Szoke J, Riely GJ et al (2008) Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis. Am J Surg Pathol 32:810–827

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Gazdar AF, Shigematsu H, Herz J et al (2004) Mutations and addiction to EGFR: the Achilles “heal” of lung cancers? Trends Mol Med 10:481–486

    Article  PubMed  CAS  Google Scholar 

  14. Camidge DR, Bang YJ, Kwak EL et al (2012) Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 13:1011–1019

    Article  PubMed  CAS  Google Scholar 

  15. Shaw AT, Kim DW, Nakagawa K, et al (2012) Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) (PROFILE 1007). European Society for Medical Oncology. Abstract: LBA-1

  16. Nowak F, Soria JC, Calvo F (2012) Tumour molecular profiling for deciding therapy—the French initiative. Nat Rev Clin Oncol 9:479–486

    Article  PubMed  CAS  Google Scholar 

  17. Azzoli CG, Baker S Jr, Temin S et al (2009) American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 27:6251–6626

    Article  PubMed  CAS  Google Scholar 

  18. 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  PubMed  CAS  Google Scholar 

  19. Wolf J, LoRusso PM, Camidge RD, et al (2012) Abstract LB-122: A phase I dose escalation study of NVP-BGJ398, a selective pan FGFR inhibitor in genetically preselected advanced solid tumors. Cancer Research 72. doi:10.1158/1538-7445.AM2012-LB-122

  20. 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  PubMed  CAS  Google Scholar 

  21. Onozato R, Kosaka T, Kuwano H et al (2009) Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol 4:5–11

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  23. Cappuzzo F, Marchetti A, Skokan M 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  Google Scholar 

  24. Otsuka T, Takayama H, Sharp R et al (1998) c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype. Cancer Res 58:5157–5167

    PubMed  CAS  Google Scholar 

  25. Kong-Beltran M, Seshagiri S, Zha J et al (2006) Somatic mutations lead to an oncogenic deletion of MET in lung cancer. Cancer Res 66:283–289

    Article  PubMed  CAS  Google Scholar 

  26. Eder JP, Vande Woude GF, Boerner SA, LoRusso PM (2009) Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res 15:2207–2214

    Article  PubMed  CAS  Google Scholar 

  27. Spigel D, Ervin T, Ramlau R et al (2011) Final efficacy results from a randomized phase II study (OAM4558g) evaluating Met Mab or placebo in combination with erlotinib in advanced NSCLC. J Thorac Oncol 6:S359

    Google Scholar 

  28. Scagliotti GV, Novello S, Schiller JH et al (2012) Rationale and design of MARQUEE: a phase III, randomized, double-blind study of tivantinib plus erlotinib versus placebo plus erlotinib in previously treated patients with locally advanced or metastatic, nonsquamous, non-small-cell lung cancer. Clin Lung Canc 13:391–395

    Article  CAS  Google Scholar 

  29. Coussens L, Yang-Feng TL, Liao YC et al (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230:1132–1139

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. Hirsch FR, Langer CJ (2004) The role of HER2/neu expression and trastuzumab in non-small cell lung cancer. Semin Oncol 31:75–82

    Article  PubMed  CAS  Google Scholar 

  32. Arcila ME, Chaft JE, Nafa K et al (2012) Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res 18:4910–4918

    Article  PubMed  CAS  Google Scholar 

  33. Perera SA, Li D, Shimamura T, Raso MG 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  PubMed  CAS  Google Scholar 

  34. De Grève 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  PubMed  Google Scholar 

  35. Mazieres J, Peters S, Cortot A, et al (2011) Lung cancer harboring HER2 mutation: epidemiological characteristics and therapeutic perspectives. European Society for Medical Oncology. Abstract: 1232PD

  36. Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  38. Jang TW, Oak CH, Chang HK et al (2009) EGFR and KRAS mutations in patients with adenocarcinoma of the lung. Kor J Intern Med 24:48–54

    Article  Google Scholar 

  39. Fisher GH, Wellen SL, Klimstra D et al (2001) Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 15:3249–3262

    Article  PubMed  CAS  Google Scholar 

  40. Adjei AA, Mauer A, Bruzek L et al (2003) Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer. J Clin Oncol 21:1760–1766

    Article  PubMed  CAS  Google Scholar 

  41. Dingemans AM, Mellema WW, Groen HJM, et al (2011) A phase II study of sorafenib in patients with locally advanced and/or metastatic (stage IIIB or IV) non-small cell lung cancer (NSCLC) with a K-Ras mutation. European Society for Medical Oncology. Abstract: LBA-27

  42. Mok TSK, Paz-Ares L, Wu YL, et al (2012) Association between tumor EGFR and KRAS mutation status and clinical outcomes in NSCLC patients randomized to sorafenib plus best supportive care (BSC) or BSC alone: subanalysis of the phase III MISSION trial. European Society for Medical Oncology. Abstract: LBA9_PR

  43. Janne PA, Shaw AT, Rodrigues Pereira J, et al. (2012) Efficacy and patient (pt)-reported outcomes with selumetinib (AZD6244, ARRY-142866; sel) + docetaxel (doc) in KRAS-mutant advanced non-small cell lung cancer (NSCLC): a randomized, phase II trial. European Society for Medical Oncology. Abstract: 1233PD

  44. 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  PubMed  CAS  Google Scholar 

  45. Jimenez C, Jones DR, Rodríguez-Viciana P et al (1998) Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. EMBO J 17:743–753

    Article  PubMed  CAS  Google Scholar 

  46. Samuels Y, Wang Z, Bardelli A et al (2004) High frequency of mutations of the PIK3CAgene in human cancers. Science 304:554

    Article  PubMed  CAS  Google Scholar 

  47. 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 

  48. Ikenoue T, Kanai F, Hikiba Y et al (2005) Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 65:4562–4567

    Article  PubMed  CAS  Google Scholar 

  49. Testa JR, Bellacosa A (2001) AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA 98:10983–10985

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  51. Leicht DT, Balan V, Kaplun A et al (2007) Raf kinases: function, regulation and role in human cancer. Biochim Biophys Acta 1773:1196–1212

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  53. Sasaki H, Kawano O, Endo K et al (2006) Uncommon V599E BRAF mutations in Japanese patients with lung cancer. J Surg Res 133:203–206

    Article  PubMed  CAS  Google Scholar 

  54. 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  Google Scholar 

  55. 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  PubMed  CAS  Google Scholar 

  56. Sen B, Peng S, Tang X et al (2012) Kinase-impaired BRAF mutations in lung cancer confer sensitivity to dasatinib. Sci Transl Med 4:136ra70

    Article  PubMed  CAS  Google Scholar 

  57. Hanna NH, Pawel JV, Reck M, Scagliotti G (2008) Carboplatin/paclitaxel with/without sorafenib in chemonaive patients with stage IIIb-IV non-small cell lung cancer: interim analysis (IA) results from a randomized phase III trial (ESCAPE). J Thorac Oncol 3:S268 (Abstract 214)

  58. Paz-Ares L, Hirsh V, Zhang L, et al (2012) Monotherapy administration of sorafenib in patients with non-small cell lung cancer: phase III, randomized, double-blind, placebo-controlled MISSION trial. European Society for Medical Oncology. Abstract: LBA33_PR

  59. Howe LR, Leevers SJ, Gómez N et al (1992) Activation of the MAP kinase pathway by the protein kinase RAF. Cell 71:335–342

    Article  PubMed  CAS  Google Scholar 

  60. Marks JL, Gong Y, Chitale D et al (2008) Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res 68:5524–5528

    Article  PubMed  CAS  Google Scholar 

  61. 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  PubMed  CAS  Google Scholar 

  62. Stumpfova M, Jänne PA (2012) Zeroing in on ROS1 rearrangements in non-small cell lung cancer. Clin Cancer Res 18:4222–4224

    Article  PubMed  CAS  Google Scholar 

  63. Rimkunas VM, Crosby KE, Li D 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 

  64. Shaw AT, Camidge DR, Engelman JA, et al (2012) Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. J Clin Oncol 30 (Abstract: 7508)

    Google Scholar 

  65. Takahashi M (1994) Ret protooncogene and human-diseases—review. Int J Oncol 4:81–84

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  67. 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  PubMed  CAS  Google Scholar 

  68. Seo JS, Ju YS, Lee WC et al (2012) The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res. doi:10.1101/gr.145144.112

  69. Ju YS, Lee WC, Shin JY 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  CAS  Google Scholar 

  70. Jeanmart M, Lantuejoul S, Fievet F et al (2003) Value of immunohistochemical markers in preinvasive bronchial lesions in risk assessment of lung cancer. Clin Cancer Res 9:2195–2203

    PubMed  CAS  Google Scholar 

  71. Jackman D, Pao W, Riely GJ et al (2010) Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 28:357–360

    Article  PubMed  CAS  Google Scholar 

  72. 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  Google Scholar 

  73. Oxnard GR, Arcila ME, Sima CS et al (2011) Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res 17:1616–1622

    Article  PubMed  CAS  Google Scholar 

  74. Godin-Heymann N, Bryant I, Rivera MN et al (2007) Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer Res 67:7319–7326

    Article  PubMed  CAS  Google Scholar 

  75. Eck MJ, Yun CH (2010) Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim Biophys Acta 1804:559–566

    Article  PubMed  CAS  Google Scholar 

  76. Maheswaran S, Sequist LV, Nagrath S et al (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359:366–377

    Article  PubMed  CAS  Google Scholar 

  77. Cortot AB, Repellin CE, Shimamura T, et al (2011) Resistance to EGFR T790M kinase inhibitors through a multistep process involving the IGF1R pathway. World Conference on Lung Cancer. Abstract: O27.01

  78. Bean J, Brennan C, Shih JY et al (2007) MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 104:20932–20937

    Article  PubMed  CAS  Google Scholar 

  79. Janjigian YY, Groen HJ, Horn L, et al (2011) Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. J Clin Oncol 29. Abstract: 7525

  80. Doebele RC, Pilling AB, Aisner DL et al (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18:1472–1482

    Article  PubMed  CAS  Google Scholar 

  81. Felip E, Carcereny E, Barlesi F, et al (2012) Phase II activity of the HSP90 inhibitor AUY922 in patients with ALK-rearranged (ALK+) or EGFR-mutated advanced non-small cell lung cancer (NSCLC). European Society for Medical Oncology. Abstract: 438O

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  84. Dong H, Strome SE, Salomao DR et al (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800

    PubMed  CAS  Google Scholar 

  85. Dong H, Zhu G, Tamada K, Chen L (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5:1365–1369

    Article  PubMed  CAS  Google Scholar 

  86. Freeman GJ, Long AJ, Iwai Y et al (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034

    Article  PubMed  CAS  Google Scholar 

  87. Brahmer JR, Tykodi SS, Chow LQ 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  CAS  Google Scholar 

  88. Brahmer JR, Drake CG, Wollner I et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28:3167–3175

    Article  PubMed  CAS  Google Scholar 

  89. Lynch TJ, Bondarenko I, Luft A et al (2012) Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 30:2046–2054

    Article  PubMed  CAS  Google Scholar 

  90. Imielinski M, Berger AH, Hammerman PS et al (2012) Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150:1107–20

    Article  PubMed  CAS  Google Scholar 

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Girard, N. Other signalization targets. Targ Oncol 8, 69–77 (2013). https://doi.org/10.1007/s11523-012-0246-5

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