Somatic Genetic Alterations and Implications for Targeted Therapies in Cancer (GIST, CML, Lung Cancer)

  • Alice T. ShawEmail author
  • Eyal C. Attar
  • Edwin Choy
  • Jeffrey Engelman


The last decade has witnessed tremendous advances in the treatment of patients with cancer. Chief among these is the discovery and successful development of new, targeted cancer therapies. These therapies are highly effective in genetically defined subsets of patients, i.e., patients whose tumors harbor specific genetic abnormalities. In contrast to previous chapters focusing on germline genetic alterations that increase the risk of cancer, this chapter will examine cancers with somatic genetic alterations that confer sensitivity to molecularly targeted therapies. Examples of targeted therapies include imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors, traztuzumab and lapatinib for HER2-amplified breast cancer, and erlotinib, a tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor (EGFR), for EGFR-mutant nonsmall cell lung cancer (see Table 15.1).


Tyrosine kinase Tyrosine kinase inhibitor Gastrointestinal stromal tumor Chronic myelogenous leukemia Lung cancer Imatinib EGFR inhibitor Philadelphia chromosome c-KIT Stem cell factor Fluorescence in situ hybridization 


  1. 1.
    Sawyers CL (1999) Chronic myeloid leukemia. N Engl J Med 340:1330–1340PubMedCrossRefGoogle Scholar
  2. 2.
    Faderl S, Talpaz M, Estrov Z et al (1999) The biology of chronic myeloid leukemia. N Engl J Med 341:164–172PubMedCrossRefGoogle Scholar
  3. 3.
    Gratwohl A, Brand R, Apperley J et al (2006) Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 91:513–521PubMedGoogle Scholar
  4. 4.
    Hehlmann R, Berger U, Pfirrmann M et al (2007) Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 109:4686–4692PubMedCrossRefGoogle Scholar
  5. 5.
    Druker BJ, Tamura S, Buchdunger E et al (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561–566PubMedCrossRefGoogle Scholar
  6. 6.
    O’Brien SG, Guilhot F, Larson RA et al (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004PubMedCrossRefGoogle Scholar
  7. 7.
    Druker BJ, Guilhot F, O’Brien SG et al (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408–2417PubMedCrossRefGoogle Scholar
  8. 8.
    Sawyers CL, Hochhaus A, Feldman E et al (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530–3539PubMedCrossRefGoogle Scholar
  9. 9.
    Talpaz M, Silver RT, Druker BJ et al (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99:1928–1937PubMedCrossRefGoogle Scholar
  10. 10.
    Novartis (2007) Imatinib prescribing information. Novartis, East Hanover, NJGoogle Scholar
  11. 11.
    O’Hare T, Eide CA, Deininger MW (2007) Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 110:2242–2249PubMedCrossRefGoogle Scholar
  12. 12.
    Soverini S, Colarossi S, Gnani A et al (2006) Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 12:7374–7379PubMedCrossRefGoogle Scholar
  13. 13.
    Branford S, Rudzki Z, Walsh S et al (2003) Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 102:276–283PubMedCrossRefGoogle Scholar
  14. 14.
    Hughes T, Deininger M, Hochhaus A et al (2006) Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 108:28–37PubMedCrossRefGoogle Scholar
  15. 15.
    Deininger M, Buchdunger E, Druker BJ (2005) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105:2640–2653PubMedCrossRefGoogle Scholar
  16. 16.
    Gorre ME, Mohammed M, Ellwood K et al (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880PubMedCrossRefGoogle Scholar
  17. 17.
    O’Hare T, Walters DK, Stoffregen EP et al (2005) In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 65:4500–4505PubMedCrossRefGoogle Scholar
  18. 18.
    Kantarjian HM, Talpaz M, Giles F et al (2006) New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med 145:913–923PubMedGoogle Scholar
  19. 19.
    Hochhaus A, Kreil S, Corbin AS et al (2002) Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16:2190–2196PubMedCrossRefGoogle Scholar
  20. 20.
    Wu J, Meng F, Lu H et al (2008) Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells. Blood 111:3821–3829PubMedCrossRefGoogle Scholar
  21. 21.
    Burchert A, Wang Y, Cai D et al (2005) Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia 19:1774–1782PubMedCrossRefGoogle Scholar
  22. 22.
    Thomas J, Wang L, Clark RE et al (2004) Active transport of imatinib into and out of cells: implications for drug resistance. Blood 104:3739–3745PubMedCrossRefGoogle Scholar
  23. 23.
    Zong Y, Zhou S, Sorrentino BP (2005) Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia. Leukemia 19:1590–1596PubMedCrossRefGoogle Scholar
  24. 24.
    Perel JM, McCarthy C, Walker O et al (2005) Clinical significance of development of Philadelphia-chromosome negative clones in patients with chronic myeloid leukemia treated with imatinib mesylate. Haematologica 90 Suppl:ECR25Google Scholar
  25. 25.
    Tokarski JS, Newitt JA, Chang CY et al (2006) The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 66:5790–5797PubMedCrossRefGoogle Scholar
  26. 26.
    Lombardo LJ, Lee FY, Chen P et al (2004) Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47:6658–6661PubMedCrossRefGoogle Scholar
  27. 27.
    Nam S, Kim D, Cheng JQ et al (2005) Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res 65:9185–9189PubMedCrossRefGoogle Scholar
  28. 28.
    Weisberg E, Manley PW, Breitenstein W et al (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7:129–141PubMedCrossRefGoogle Scholar
  29. 29.
    le Coutre P, Ottmann OG, Giles F et al (2008) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 111:1834–1839PubMedCrossRefGoogle Scholar
  30. 30.
    Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 130:1466–1478PubMedGoogle Scholar
  31. 31.
    Blanke CD, Eisenberg BL, Heinrich MC (2001) Gastrointestinal stromal tumors. Curr Treat Options Oncol 2:485–491PubMedCrossRefGoogle Scholar
  32. 32.
    Corless CL, Fletcher JA, Heinrich MC (2004) Biology of gastrointestinal stromal tumors. J Clin Oncol 22:3813–3825PubMedCrossRefGoogle Scholar
  33. 33.
    Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 23:70–83PubMedCrossRefGoogle Scholar
  34. 34.
    Rubin BP, Heinrich MC, Corless CL (2007) Gastrointestinal stromal tumour. Lancet 369:1731–1741PubMedCrossRefGoogle Scholar
  35. 35.
    Somerhausen Nde S, Fletcher CD (1998) Gastrointestinal stromal tumours: an update. Sarcoma 2:133–141CrossRefGoogle Scholar
  36. 36.
    Sarlomo-Rikala M, Kovatich AJ, Barusevicius A et al (1998) CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol 11:728–734PubMedGoogle Scholar
  37. 37.
    Heinrich MC, Dooley DC, Freed AC et al (1993) Constitutive expression of steel factor gene by human stromal cells. Blood 82:771–783PubMedGoogle Scholar
  38. 38.
    Rubin BP, Singer S, Tsao C et al (2001) KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61:8118–8121PubMedGoogle Scholar
  39. 39.
    Corless CL, Heinrich MC (2008) Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol 3:557–586PubMedCrossRefGoogle Scholar
  40. 40.
    Fletcher JA, Fletcher CD, Rubin BP et al (2002) KIT gene mutations in gastrointestinal stromal tumors: more complex than previously recognized? Am J Pathol 161:737–738, author reply 738–739PubMedCrossRefGoogle Scholar
  41. 41.
    Hirota S, Isozaki K, Moriyama Y et al (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580PubMedCrossRefGoogle Scholar
  42. 42.
    Heinrich MC, Corless CL, Duensing A et al (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299: 708–710PubMedCrossRefGoogle Scholar
  43. 43.
    Lasota J, Stachura J, Miettinen M (2006) GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology. Lab Invest 86:94–100PubMedCrossRefGoogle Scholar
  44. 44.
    Carroll M, Ohno-Jones S, Tamura S et al (1997) CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 90:4947–4952PubMedGoogle Scholar
  45. 45.
    Druker BJ, Talpaz M, Resta DJ et al (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037PubMedCrossRefGoogle Scholar
  46. 46.
    Topaly J, Zeller WJ, Fruehauf S (2001) Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells. Leukemia 15:342–347PubMedCrossRefGoogle Scholar
  47. 47.
    Heinrich MC, Griffith DJ, Druker BJ et al (2000) Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96:925–932PubMedGoogle Scholar
  48. 48.
    Tuveson DA, Willis NA, Jacks T et al (2001) STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 20:5054–5058PubMedCrossRefGoogle Scholar
  49. 49.
    Joensuu H, Roberts PJ, Sarlomo-Rikala M et al (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056PubMedCrossRefGoogle Scholar
  50. 50.
    van Oosterom AT, Judson I, Verweij J et al (2001) Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358:1421–1423PubMedCrossRefGoogle Scholar
  51. 51.
    Blanke CD, Demetri GD, von Mehren M et al (2008) Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 26:620–625PubMedCrossRefGoogle Scholar
  52. 52.
    Demetri GD, Desai J, Fletcher JA et al (2004) SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib resistance caused by diverse genomic mechanisms in patients with metastatic gastrointestinal stromal tumor. Proc Am Soc Clin Oncol 22:195sGoogle Scholar
  53. 53.
    Demetri GD, van Oosterom AT, Garrett CR et al (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368:1329–1338PubMedCrossRefGoogle Scholar
  54. 54.
    Heinrich MC, Corless CL, Demetri GD et al (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349PubMedCrossRefGoogle Scholar
  55. 55.
    Heinrich MC, Corless CL, Blanke CD et al (2006) Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24:4764–4774PubMedCrossRefGoogle Scholar
  56. 56.
    Antonescu CR, Besmer P, Guo T et al (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11:4182–4190PubMedCrossRefGoogle Scholar
  57. 57.
    Heinrich MC, Maki RG, Corless CL et al (2008) Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 26:5352–5359PubMedCrossRefGoogle Scholar
  58. 58.
    Duensing A, Medeiros F, McConarty B et al (2004) Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 23:3999–4006PubMedCrossRefGoogle Scholar
  59. 59.
    Duensing A, Heinrich MC, Fletcher CD et al (2004) Biology of gastrointestinal stromal tumors: KIT mutations and beyond. Cancer Invest 22:106–116PubMedCrossRefGoogle Scholar
  60. 60.
    Liegl B, Kepten I, Le C et al (2008) Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol 216:64–74PubMedCrossRefGoogle Scholar
  61. 61.
    McArthur GA, Demetri GD, van Oosterom A et al (2005) Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225. J Clin Oncol 23:866–873PubMedCrossRefGoogle Scholar
  62. 62.
    Mehrany K, Swanson NA, Heinrich MC et al (2006) Dermatofibrosarcoma protuberans: a partial response to imatinib therapy. Dermatol Surg 32:456–459PubMedCrossRefGoogle Scholar
  63. 63.
    Beadling C, Jacobson-Dunlop E, Hodi FS et al (2008) KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res 14:6821–6828PubMedCrossRefGoogle Scholar
  64. 64.
    Hodi FS, Friedlander P, Corless CL et al (2008) Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26:2046–2051PubMedCrossRefGoogle Scholar
  65. 65.
    Jiang X, Zhou J, Yuen NK et al (2008) Imatinib targeting of KIT-mutant oncoprotein in melanoma. Clin Cancer Res 14:7726–7732PubMedCrossRefGoogle Scholar
  66. 66.
    Heinrich MC, Corless CL (2004) Targeting mutant kinases in gastrointestinal stromal tumors: a paradigm for molecular therapy of other sarcomas. Cancer Treat Res 120:129–150PubMedCrossRefGoogle Scholar
  67. 67.
    Demetri GD (2001) Targeting c-kit mutations in solid tumors: scientific rationale and novel therapeutic options. Semin Oncol 28:19–26PubMedCrossRefGoogle Scholar
  68. 68.
    Heinrich MC, Blanke CD, Druker BJ et al (2002) Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20:1692–1703PubMedCrossRefGoogle Scholar
  69. 69.
    Schiller JH, Harrington D, Belani CP et al (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98PubMedCrossRefGoogle Scholar
  70. 70.
    Laskin JJ, Sandler AB (2004) Epidermal growth factor receptor: a promising target in solid tumours. Cancer Treat Rev 30:1–17PubMedCrossRefGoogle Scholar
  71. 71.
    Brabender J, Danenberg KD, Metzger R et al (2001) Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival. Clin Cancer Res 7:1850–1855PubMedGoogle Scholar
  72. 72.
    Fontanini G, De Laurentiis M, Vignati S et al (1998) Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival. Clin Cancer Res 4:241–249PubMedGoogle Scholar
  73. 73.
    Ohsaki Y, Tanno S, Fujita Y et al (2000) Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. Oncol Rep 7:603–607PubMedGoogle Scholar
  74. 74.
    Rusch V, Baselga J, Cordon-Cardo C et al (1993) Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 53:2379–2385PubMedGoogle Scholar
  75. 75.
    Rusch V, Klimstra D, Venkatraman E et al (1997) Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression. Clin Cancer Res 3:515–522PubMedGoogle Scholar
  76. 76.
    Volm M, Rittgen W, Drings P (1998) Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and Myc in patients with squamous cell lung carcinomas. Br J Cancer 77:663–669PubMedCrossRefGoogle Scholar
  77. 77.
    Carraway KL 3rd, Cantley LC (1994) A neu acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling. Cell 78:5–8PubMedCrossRefGoogle Scholar
  78. 78.
    Riese DJ 2nd, Stern DF (1998) Specificity within the EGF family/ErbB receptor family signaling network. Bioessays 20:41–48PubMedCrossRefGoogle Scholar
  79. 79.
    Roskoski R Jr (2004) The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun 319:1–11PubMedCrossRefGoogle Scholar
  80. 80.
    Kawamoto T, Sato JD, Le A et al (1983) Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci USA 80:1337–1341PubMedCrossRefGoogle Scholar
  81. 81.
    Sirotnak FM (2003) Studies with ZD1839 in preclinical models. Semin Oncol 30:12–20PubMedCrossRefGoogle Scholar
  82. 82.
    Baselga J, Rischin D, Ranson M et al (2002) Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20:4292–4302PubMedCrossRefGoogle Scholar
  83. 83.
    Herbst RS, Maddox AM, Rothenberg ML et al (2002) Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol 20:3815–3825PubMedCrossRefGoogle Scholar
  84. 84.
    Ranson M, Hammond LA, Ferry D et al (2002) ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 20:2240–2250PubMedCrossRefGoogle Scholar
  85. 85.
    Nakagawa K, Tamura T, Negoro S et al (2003) Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid malignant tumors. Ann Oncol 14:922–930PubMedCrossRefGoogle Scholar
  86. 86.
    Fukuoka M, Yano S, Giaccone G et al (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237–2246PubMedCrossRefGoogle Scholar
  87. 87.
    Kris MG, Natale RB, Herbst RS et al (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290:2149–2158PubMedCrossRefGoogle Scholar
  88. 88.
    Shepherd FA, Pereira J, Ciuleanu TE et al (2004) A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. Proc Am Soc Clin Oncol 622sGoogle Scholar
  89. 89.
    Thatcher N, Chang A, Parikh P et al (2005) Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527–1537PubMedCrossRefGoogle Scholar
  90. 90.
    Miller VA, Kris MG, Shah N et al (2004) Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22:1103–1109PubMedCrossRefGoogle Scholar
  91. 91.
    Janne PA, Gurubhagavatula S, Yeap BY et al (2004) Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, ‘Iressa’) on an expanded access study. Lung Cancer 44:221–230PubMedCrossRefGoogle Scholar
  92. 92.
    Haringhuizen A, van Tinteren H, Vaessen HF et al (2004) Gefitinib as a last treatment option for non-small-cell lung cancer: durable disease control in a subset of patients. Ann Oncol 15:786–792PubMedCrossRefGoogle Scholar
  93. 93.
    Simon GR, Ruckdeschel JC, Williams C et al (2003) Gefitinib (ZD1839) in previously treated advanced non-small-cell lung cancer: experience from a single institution. Cancer Control 10:388–395PubMedGoogle Scholar
  94. 94.
    Argiris A, Mittal N (2004) Gefitinib as first-line, compassionate use therapy in patients with advanced non-small-cell lung cancer. Lung Cancer 43:317–322PubMedCrossRefGoogle Scholar
  95. 95.
    Park J, Park BB, Kim JY et al (2004) Gefitinib (ZD1839) monotherapy as a salvage regimen for previously treated advanced non-small cell lung cancer. Clin Cancer Res 10:4383–4388PubMedCrossRefGoogle Scholar
  96. 96.
    Lynch TJ, Bell DW, Sordella R 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 350:2129–2139PubMedCrossRefGoogle Scholar
  97. 97.
    Paez JG, Janne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500PubMedCrossRefGoogle Scholar
  98. 98.
    Pao W, Miller V, Zakowski M 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 USA 101:13306–13311PubMedCrossRefGoogle Scholar
  99. 99.
    Inoue A, Suzuki T, Fukuhara T et al (2006) Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 24:3340–3346PubMedCrossRefGoogle Scholar
  100. 100.
    Okamoto I, Kashii T, Urata Y et al (2006) EGFR mutation-based phase II multicenter trial of gefitinib in advanced non-small cell lung cancer (NSCLC) patients (pts): Results of West Japan Thoracic Oncology Group trial (WJTOG0403). J Clin Oncol 24:Absract 7073Google Scholar
  101. 101.
    Sutani A, Nagai Y, Udagawa K et al (2006) Phase II study of gefitinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) gene mutations detected by PNA-LNA PCR clamp. J Clin Oncol 24:Abstract 7076Google Scholar
  102. 102.
    Morikawa N, Inoue A, Suzuki T et al (2006) Prospective analysis of the epidermal growth factor receptor gene mutations in non-small cell lung cancer in Japan. J Clin Oncol 24:Abstract 7077Google Scholar
  103. 103.
    Sequist LV, Martins RG, Spigel D et al (2008) First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 26:2442–2449PubMedCrossRefGoogle Scholar
  104. 104.
    Mok T, Wu Y-L, Thongprasert S et al (2008) Phase III, randomised, open-label, first-line study of gefitinib vs carboplatin/paclitaxel in clinically selected patients with advanced non-small cell lung cancer (IPASS). 33rd ESMO congress, StockholmGoogle Scholar
  105. 105.
    Tsao MS, Sakurada A, Cutz JC et al (2005) Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Engl J Med 353:133–144PubMedCrossRefGoogle Scholar
  106. 106.
    Engelman JA, Zejnullahu K, Mitsudomi T et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043PubMedCrossRefGoogle Scholar
  107. 107.
    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 116:2695–2706PubMedCrossRefGoogle Scholar
  108. 108.
    Tracy S, Mukohara T, Hansen M et al (2004) Gefitinib induces apoptosis in the EGFRL858R non-small cell lung cancer cell line H3255. Cancer Res 64:7241–7244PubMedCrossRefGoogle Scholar
  109. 109.
    Smolen GA, Sordella R, Muir B et al (2006) Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci USA 103:2316–2321PubMedCrossRefGoogle Scholar
  110. 110.
    Engelman JA (2007) The role of phosphoinositide 3-kinase pathway inhibitors in the treatment of lung cancer. Clin Cancer Res 13:s4637–s4640PubMedCrossRefGoogle Scholar
  111. 111.
    She Q, Solit D, Ye Q et al (2005) The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 8:287–297PubMedCrossRefGoogle Scholar
  112. 112.
    Mellinghoff IK, Wang MY, Vivanco I et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024PubMedCrossRefGoogle Scholar
  113. 113.
    Sharma SV, Fischbach MA, Haber DA et al (2006) “Oncogenic shock”: explaining oncogene addiction through differential signal attenuation. Clin Cancer Res 12:4392s–4395sPubMedCrossRefGoogle Scholar
  114. 114.
    Engelman JA, Settleman J (2008) Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr Opin Genet Dev 18:73–79PubMedCrossRefGoogle Scholar
  115. 115.
    Engelman JA, Janne PA (2008) Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 14: 2895–2899PubMedCrossRefGoogle Scholar
  116. 116.
    Kobayashi S, Boggon TJ, Dayaram T et al (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792PubMedCrossRefGoogle Scholar
  117. 117.
    Pao W, Miller VA, Politi KA et al (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:1–11CrossRefGoogle Scholar
  118. 118.
    Kosaka T, Yatabe Y, Endoh H et al (2006) Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res 12:5764–5769PubMedCrossRefGoogle Scholar
  119. 119.
    Balak MN, Gong Y, Riely GJ 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 12:6494–6501PubMedCrossRefGoogle Scholar
  120. 120.
    Kwak EL, Sordella R, Bell DW et al (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102:7665–7670PubMedCrossRefGoogle Scholar
  121. 121.
    Kobayashi S, Ji H, Yuza Y et al (2005) An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res 65:7096–7101PubMedCrossRefGoogle Scholar
  122. 122.
    Li D, Shimamura T, Ji H et al (2007) Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell 12:81–93PubMedCrossRefGoogle Scholar
  123. 123.
    Regales L, Balak MN, Gong Y et al (2007) Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. PLoS One 2:e810PubMedCrossRefGoogle Scholar
  124. 124.
    Ogino A, Kitao H, Hirano S et al (2007) Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non small cell lung cancer cell line. Cancer Res 67:7807–7814PubMedCrossRefGoogle Scholar
  125. 125.
    Cappuzzo F, Hirsch FR, Rossi E et al (2005) Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643–655PubMedCrossRefGoogle Scholar
  126. 126.
    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 67:7319–7326PubMedCrossRefGoogle Scholar
  127. 127.
    Greulich H, Chen TH, Feng W et al (2005) Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2:e313PubMedCrossRefGoogle Scholar
  128. 128.
    Bell DW, Gore I, Okimoto RA et al (2005) Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet 37:1315–1316PubMedCrossRefGoogle Scholar
  129. 129.
    Kosaka T, Yatabe Y, Endoh H et al (2004) Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 64:8919–8923PubMedCrossRefGoogle Scholar
  130. 130.
    Engelman JA, Zejnullahu K, Gale CM et al (2007) PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 67:11924–11932PubMedCrossRefGoogle Scholar
  131. 131.
    Janne PA, Schellens JH, Engelman JA et al (2008) Preliminary activity and safety results from a phase I clinical trial of PF-00299804, an irreversible pan-HER inhibitor, in patients (pts) with NSCLC (Abstract #8027). J Clin Oncol 26:Abstract 8027Google Scholar
  132. 132.
    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 USA 104:20932–20937PubMedCrossRefGoogle Scholar
  133. 133.
    Soda M, Choi YL, Enomoto M et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566PubMedCrossRefGoogle Scholar
  134. 134.
    Rikova K, Guo A, Zeng Q et al (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131:1190–1203PubMedCrossRefGoogle Scholar
  135. 135.
    Chiarle R, Voena C, Ambrogio C et al (2008) The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 8:11–23PubMedCrossRefGoogle Scholar
  136. 136.
    Soda M, Takada S, Takeuchi K et al (2008) A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci USA 105:19893–19897PubMedCrossRefGoogle Scholar
  137. 137.
    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 14:4275–4283PubMedCrossRefGoogle Scholar
  138. 138.
    McDermott U, Iafrate AJ, Gray NS et al (2008) Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 68:3389–3395PubMedCrossRefGoogle Scholar
  139. 139.
    Fukuyoshi Y, Inoue H, Kita Y et al (2008) EML4-ALK fusion transcript is not found in gastrointestinal and breast cancers. Br J Cancer 98:1536–1539PubMedCrossRefGoogle Scholar
  140. 140.
    Takeuchi K, Choi YL, Soda M et al (2008) Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res 14:6618–6624PubMedCrossRefGoogle Scholar
  141. 141.
    Perner S, Wagner PL, Demichelis F et al (2008) EML4-ALK fusion lung cancer: a rare acquired event. Neoplasia 10: 298–302PubMedGoogle Scholar
  142. 142.
    Inamura K, Takeuchi K, Togashi Y et al (2008) EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol 3:13–17PubMedCrossRefGoogle Scholar
  143. 143.
    Shinmura K, Kageyama S, Tao H et al (2008) EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. Lung Cancer 61:163–169PubMedCrossRefGoogle Scholar
  144. 144.
    Wong DW, Leung EL, So KK 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(8): 1723–1733PubMedCrossRefGoogle Scholar
  145. 145.
    Shaw AT, Yeap BY, Mino-Kenudson M et al (2009) Clinical features and outcome of patients with non-small cell lung cancer harboring EML4-ALK. J Clin Oncol 27(26):4247–4253PubMedCrossRefGoogle Scholar
  146. 146.
    Castro CY, Moran CA, Flieder DG et al (2001) Primary signet ring cell adenocarcinomas of the lung: a clinicopathological study of 15 cases. Histopathology 39:397–401PubMedCrossRefGoogle Scholar
  147. 147.
    Tsuta K, Ishii G, Yoh K et al (2004) Primary lung carcinoma with signet-ring cell carcinoma components: clinicopathological analysis of 39 cases. Am J Surg Pathol 28:868–874PubMedCrossRefGoogle Scholar
  148. 148.
    Iwasaki T, Ohta M, Lefor AT et al (2008) Signet-ring cell carcinoma component in primary lung adenocarcinoma: potential prognostic factor. Histopathology 52:639–640PubMedCrossRefGoogle Scholar
  149. 149.
    Christensen JG, Zou HY, Arango ME et al (2007) Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 6:3314–3322PubMedCrossRefGoogle Scholar
  150. 150.
    Kwak EL, Camidge DR, Clark J et al (2009) Clinical activity observed in a phase I dose-escalation trial of an oral c-Met and ALK inhibitor, PF-02341066. J Clin Oncol 27:15sCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Alice T. Shaw
    • 1
    Email author
  • Eyal C. Attar
  • Edwin Choy
  • Jeffrey Engelman
  1. 1.Massachusetts General Hospital Cancer Center, Harvard Medical SchoolBostonUSA

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