Current Oncology Reports

, Volume 14, Issue 2, pp 105–110

The Biology and Clinical Features of Non–small Cell Lung Cancers with EML4-ALK Translocation

Evolving Therapies (RM Bukowski, Section Editor)

Abstract

The anaplastic lymphoma kinase (ALK) acts as a dominant oncogenic driver following chromosomal rearrangements in certain cancers including non–small cell lung cancer (NSCLC). NSCLC with ALK translocation occurs in a specific subset of patients and results in unique clinical features. Crizotinib is a small molecule inhibitor of ALK kinase that has recently been approved by the FDA for the treatment of patients with ALK-positive NSCLC. Treatment with crizotinib results in clinical benefit rate of 85%–90% and a median progression-free survival of 9–10 months for this molecular subset of patients. Ongoing studies will define the impact of crizotinib on overall survival and provide insights into the resistance mechanisms and potential activation of alternate pathways. Heat shock protein 90 inhibitors also appear promising in the treatment of ALK-positive NSCLC patients, based on early results. This article reviews the characteristics, treatment, and ongoing research in patients with ALK-positive NSCLC.

Keywords

EML4-ALK translocation Non-small cell lung cancer (NSCLC) Crizotinib Heat shock protein 90 (Hsp90) IPI-504 Ganetespib 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Ambrogio C, Voena C, Manazza AD, et al. The anaplastic lymphoma kinase controls cell shape and growth of anaplastic large cell lymphoma through Cdc42 activation. Cancer Res. 2008;68(21):8899–907.PubMedCrossRefGoogle Scholar
  2. 2.
    Chiarle R, Voena C, Ambrogio C, et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8(1):11–23.PubMedCrossRefGoogle Scholar
  3. 3.
  4. 4.
    Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Mok TS, Wu YL, Thongprasert S. Phase III, randomised, open-label, first-line study of gefitinib vs carboplatin/paclitaxel in clinically selected patients with advanced nonsmall-cell lung cancer (IPASS). . in ESMO Conference. 2008. Stockholm.Google Scholar
  6. 6.
    Rosell R, Gervais R, Vergnenegre A, et al, Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutaitons: Interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial, in ASCO. 2011: Chicago.Google Scholar
  7. 7.
    • Soda M, Choi YL, Enomoto M, et al., Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature, 2007. 448(7153): p. 561-6. This is the initial report describing the identification of the EML4-ALK translocation in a lung adenocarcinoma patient and the transforming activity of the resulting constitutively activated kinase. Google Scholar
  8. 8.
    Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A. 2008;105(50):19893–7.PubMedCrossRefGoogle Scholar
  9. 9.
    • Shaw, AT, Yeap BY, Mino-Kenudson M, et al., Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol, 2009. 27(26): p. 4247-53. This paper describes the clinical features of the largest cohort to date of ALK-rearranged lung cancer patients. Google Scholar
  10. 10.
    Sasaki T, Rodig SJ, Chirieac LR, Janne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46(10):1773–80.PubMedCrossRefGoogle Scholar
  11. 11.
    Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5):339–46.PubMedCrossRefGoogle Scholar
  12. 12.
    Takahashi T, Sonobe M, Kobayashi M, et al. Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol. 2010;17(3):889–97.PubMedCrossRefGoogle Scholar
  13. 13.
    Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol. 2008;3(1):13–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Annals of Surgical Oncology. 2010;17(3):889–97.CrossRefGoogle Scholar
  15. 15.
    Inamura K, Takeuchi K, Yogashi Y, et al. EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol. 2009;22(4):508–15.PubMedCrossRefGoogle Scholar
  16. 16.
    Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res. 2009;15(16):5216–23.PubMedCrossRefGoogle Scholar
  17. 17.
    Yang J, Zhang X, Su J, et al. Concomitant EGFR mutation and EML4-ALK gene fusion in non-small cell lung cancer. in ASCO. 2011. Chicago.Google Scholar
  18. 18.
    Paik JH, Choe G, Kim H, et al. Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: correlation with fluorescence in situ hybridization. J Thorac Oncol. 2011;6(3):466–72.PubMedCrossRefGoogle Scholar
  19. 19.
    Yi ES, Boland JM, Maleszewski JJ, et al. Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. J Thorac Oncol. 2011;6(3):459–65.PubMedCrossRefGoogle Scholar
  20. 20.
    Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008;14(20):6618–24.PubMedCrossRefGoogle Scholar
  21. 21.
    Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14(13):4275–83.PubMedCrossRefGoogle Scholar
  22. 22.
    • Kwak EL, Bang YJ, Camidge DR, et al., Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med, 2010. 363(18): p. 1693-703. This article reports initial phase 1 data demonstrating the therapeutic efficacy of ALK blockade by crizotinib. Google Scholar
  23. 23.
    Camidge DR, Bang Y, Kwak EL, et al. Progression-Free Survival (PFS) from a Phase 1 Study of Crizotinib (PF-02341066) in Patients with ALK-Positive Non-Small Cell Lung Cancer (NSCLC). in ASCO. 2011. Chicago.Google Scholar
  24. 24.
    Shaw AT, Yeap BY, Solomon BJ, et al, Impact of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls, in ASCO. 2011: Chicago.Google Scholar
  25. 25.
    Crino L, Kim D, Riely GJ, et al, Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005, in ASCO. 2011: Chicago.Google Scholar
  26. 26.
    Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363(18):1734–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Katayama R, Khan YM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011;108(18):7535–40.PubMedCrossRefGoogle Scholar
  28. 28.
    Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011;19(5):679–90.PubMedCrossRefGoogle Scholar
  29. 29.
    Sequist LV, Gettinger S, Senzer NN, et al. Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol. 2010;28(33):4953–60.PubMedCrossRefGoogle Scholar
  30. 30.
    Normant E, Paez G, West KA, et al. The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene. 2011;30(22):2581–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Wong K, Koczywas M, Goldman JW, et al, An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC), in ASCO. 2011: Chicago.Google Scholar
  32. 32.
    Kris MG, Johnson BE, Kwiatkowski DJ, et al. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC), in ASCO. 2011: Chicago.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Hematology and Medical OncologyEmory UniversityAtlantaUSA
  2. 2.Department of Hematology and Medical Oncology, Emory University, Winship Cancer InstituteAtlantaUSA

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