EML4-ALK Fusion Gene in Patients with Lung Carcinoma: Biology, Diagnostics and Targeted Therapy


Authors: A. Vašíková
Authors‘ workplace: Centrum molekulární biologie a genové terapie, Interní hematologická a onkologická klinika LF MU a FN Brno
Published in: Klin Onkol 2012; 25(6): 434-439
Category: Reviews

Autorka deklaruje, že v souvislosti s předmětem studie nemá žádné komerční zájmy.

Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do bi omedicínských časopisů.

Overview

Targeted therapy currently represents one of possible treatment strategies for lung cancer. High efficacy is achieved by specific inhibition of the target which is abnormally activated in a tumor cell and plays a key role in oncogenesis. EML4-ALK fusion gene, first described five years ago in patients with lung adenocarcinoma, undoubtedly has oncogenic potential and represents a promising candidate for targeted therapy. EML4-ALK fusion occurs due to paracentric inversion in the short arm of chromosome 2 and is detected in 3–5% of patients with non-small cell lung cancer. Moreover, additional fusion partners of ALK gene have been identified: TGF, KIF5B and KLC1. Targeted inhibition of constitutively activated ALK kinase mediated by crizotinib in patients positive for ALK gene rearrangements resulted in remarkable treatment response (57%) with minimal toxicity. Nevertheless, loss of response during crizotinib treatment was reported recently due to development of two resistant mutations (C1156Y and L1196M) within the kinase domain of the fusion protein. Therefore, novel, highly specific inhibitors able to overcome resistance of mutated EML4-ALK are needed. Molecular diagnostics plays an essential role in selection of suitable patients for targeted therapy and offers various methods for detection of ALK gene rearrangements. Identification of tumor-associated genetic changes together with development of novel molecular inhibitors shifts the treatment of oncologic patients towards individualized therapy.

Key words:
EML4-ALK fusion protein – non-small cell lung cancer – molecular diagnostics – molecular targeted therapy – protein kinase inhibitors – crizotinib


Sources

1. Heneberg P. Zpřesněme indikaci podávání inhibitorů kinázové aktivity EGFR. Klin Onkol 2010; 24(2): 87–93.

2. Skřičková J, Babičková L, Tomíšková M et al. Biologická léčba nemalobuněčného karcinomu plic. Interní Med 2011; 13(7,8): 292–295.

3. Zatloukal P. Biologická léčba nemalobuněčného karcinomu plic. Onkologie 2009; 3(5): 292–296.

4. Paez JG, Jänne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304(5676): 1497–1500.

5. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361(10): 947–957.

6. Fukuoka M, Wu YL, Thongprasert S et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011; 29(21): 2866–2874.

7. Zemanová M. Gefitinib v monoterapii u nemocných s pokročilým NSCLC nesoucím aktivující mutaci EGFR zlepšuje významně léčebné výsledky oproti standardní chemoterapii – aktualita z klinické praxe. Klin Onkol 2010; 23(5): 365–366.

8. Mitsudomi T, Morita S, Yatabe Y et al. 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 2010; 11(2): 121–128.

9. Zhou C, Wu YL, Chen G et al. 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 2011; 12(8): 735–742.

10. Rosell R, Carcereny E, Gervais R et al. 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 2012; 13(3): 239–246.

11. Cohen MH, Gootenberg J, Keegan P et al. FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist 2007; 12(6): 713–718.

12. 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): 561–566.

13. Pollmann M, Parwaresch R, Adam-Klages S et al. Human EML4, a novel member of the EMAP family, is essential for microtubule formation. Exp Cell Res 2006; 312(17): 3241–3251.

14. Iwahara T, Fujimoto J, Wen D et al. Molecular characterization of ALK, a receptor tyrosine kinase expresssed specifically in the nervous system. Oncogene 1997; 14(4): 439–449.

15. Morris SW, Kirstein MN, Valentine MB et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994; 263(5151): 1281–1284.

16. Griffin CA, Hawkins AL, Dvorak C et al. Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res 1999; 59(12): 2776–2780.

17. Arber DA, Sun LH, Weiss LM. Detection of the t(2;5)(p23;q35) chromosomal translocation in large B-cell lymphomas other than anaplastic large cell lymphoma. Hum Pathol 1996; 27(6): 590–594.

18. Sugawara E, Togashi Y, Kuroda N et al. Identification of anaplastic lymphoma kinase fusions in renal cancer: Large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method. Cancer 2012; 118(18): 4427–4436.

19. Lin E, Li L, Guan Y et al. Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers. Mol Cancer Res 2009; 7(9):1466–1476.

20. Chen Y, Takita J, Choi YL et al. Oncogenic mutations of ALK kinase in neuroblastoma. Nature 2008; 455(7215): 971–974.

21. Takeuchi K, Choi YL, Soda M et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res 2008; 14(20): 6618–6624.

22. Koivunen JP, Mermal 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): 4275–4283.

23. Sasaki T, Rodig SJ, Chirieac LR et al. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 2010; 46(10): 1773–1780.

24. Choi YL, Takeuchi K, Soda M et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res 2008; 68(13):4971–4976.

25. Rikova K, Guo A, Zeng Q et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007; 131(6): 1190–1203.

26. Takeuchi K, Choi YL, Togashi Y et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 2009; 15(9): 3143–3149.

27. Togashi Y, Soda M, Sakata S et al. KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One 2012; 7(2): e31323.

28. Soda M, Takada S, Takeuchi K et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci USA 2008; 105(50): 19893–19897.

29. Perner S, Wagner PL, Demichelis F et al. EML4-ALK fusion lung cancer: a rare acquired event. Neoplasia 2008; 10(3): 298–302.

30. Fukuyoshi Y, Inoue H, Kita Y et al. EML4-ALK fusion transcript is not found in gastrointestinal and breast cancers. Br J Cancer 2008; 98(9): 1536–1539.

31. 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): 13–17.

32. Martelli MP, Sozzi G, Hernandez L et al. EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am J Pathol 2009; 174(2): 661–670.

33. 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): 5216–5223.

34. Jin G, Jeon HS, Lee EB et al. EML4-ALK fusion gene in Korean non-small cell lung cancer. J Korean Med Sci 2012; 27(2): 228–230.

35. 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): 4247–4253.

36. Zhang X, Zhang S, Yang X et al. Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. Mol Cancer 2010; 9: 188.

37. Camidge DR, Kono SA, Flacco A et al. Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. Clin Cancer Res 2010; 16(22): 5581–5590.

38. 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): 459–465.

39. Sanders HR, Li HR, Bruey JM et al. Exon scanning by reverse transcriptase-polymerase chain reaction for detection of known and novel EML4-ALK fusion variants in non-small cell lung cancer. Cancer Genet 2011; 204(1): 45–52.

40. Mino-Kenudson M, Chirieac LR, Law K et al. A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res 2010; 16(5): 1561–1571.

41. Li Y, Ye X, Liu J et al. Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors. Neoplasia 2011; 13(1): 1–11.

42. 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): 1693–1703.

43. Balak MN, Gong Y, Riely GJ et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006; 12(21): 6494–6501.

44. 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): 1734–1739.

45. Katayama R, Khan TM, 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 USA 2011; 108(18): 7535–7540.

46. 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): 679–690.

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Paediatric clinical oncology Surgery Clinical oncology
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