Küçük Hücreli Dışı Akciğer Kanserinde Anaplastik Lenfoma Kinaz Gen Yeniden Düzenlemelerinin Önemi

Öz

Tedavi alanındaki tüm gelişmelere rağmen, akciğer kanseri hala tüm dünyada kanserle ilişkili ölüm nedenlerinin başında gelmektedir. Etyolojisinde sigaranın yanı sıra çevresel, mesleksel ve genetik faktörler rol oynamaktadır. Akciğer kanserleri genellikle kü- çük hücreli akciğer kanseri (KHAK) ve küçük hücreli dışı akciğer kanseri (KHDAK) olmak üzere iki ana histolojik tipe ayrılır. Tüm akciğer kanserlerinin yaklaşık %85’ini oluşturan KHDAK’inde bir- çok gen anomalisi saptanır. Anaplastik lenfoma kinaz (ALK) geni insülin reseptör tirozin kinaz süper ailesinin bir üyesidir. ALK geni akciğer kanseri, lenfoma gibi çeşitli malignitelerde füsyon protein oluşumuna yol açan translokasyonlara dahil olur. Bu derlemede KHDAK’inde görülen ALK yeniden düzenlenmelerine ait son literatür gözden geçirilecektir.

Anahtar Kelimeler

• akciğer kanseri; küçük hücreli dışı akciğer kanseri; ALK geni; gen yeniden düzenlenmeleri; EML4/ALK füzyon

Importance of Anaplastic Lymphoma Kinase Gene Re-arrangements on Non-Small Cell Lung Cancer

Öz

Despite all improvements in treatment modalities, lung cancer is the leading cause of death related to cancers worldwide. Environmental, occupational and genetic factors, as well as smoking play role in the etiology. Lung cancers are generally divided into two main histologic categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Several gene aberrations are detected in NSCLC, which constitute approximately 85% of all lung cancers. The Anaplastic lymphoma kinase (ALK) gene is a member of insulin receptor tyrosine kinase super family. ALK gene involves with translocation those results in formation of fusion protein in various malignancies such as lung cancer and lymphoma. In this article, latest literature regarding re-arrangement of ALK seen in NSCLC will be reviewed.

Anahtar Kelimeler

• lung cancer; non-small cell lung cancer; ALK gene; gene rearrangements; EML4/ALK fusion

Kaynakça

1. 1. Reungwetwattana T, Dy GK. Targeted therapies in development for non-small cell lung cancer. J Carcinog 2013;12:22.
2. 2. Aisner DL, Marshall C. Molecular pathology of non-small cell lung cancer: a practical guide. Am J Clin Pathol 2012;138:332–46.
3. 3. Vijayalakshmi R, Krishnamurthy A. Targetable “driver” mutations in non small cell lung cancer. Indian J Surg Oncol 2011;2:178–88.
4. 4. Shackelford RE, Vora M, Mayhall K, Cotelingam J. ALKrearrangements and testing methods in non-small cell lung cancer: a review. Genes Cancer 2014;5:1–14.
5. 5. Pikor LA, Ramnarine VR, Lam S, Lam WL. Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer 2013;82:179–89.
6. 6. Roskoski R Jr. Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition. Pharmacol Res 2013;68:68–94.
7. 7. Morris SW, Kirstein MN, Valentine MB, Dittmer K, Shapiro DN, Look AT, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Sci 1994;263(5151):1281–4.
8. 8. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561–6.

9. 9. Zhang X, Zhang S, Yang X, Yang J, Zhou Q, Yin L, 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.
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.
11. 11. Wangari-Talbot J, Hopper-Borge E. Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma. J Can Res Updates 2013;2:265–82.
12. 12. Tanimoto A, Yamada T, Nanjo S, Takeuchi S, Ebi H, Kita K, et al. Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells. Oncotarget 2014;5:4920–8.
13. 13. Takeda M, Okamoto I, Sakai K, Kawakami H, Nishio K, Nakagawa K. Clinical outcome for EML4-ALK-positive patients with advanced non-small-cell lung cancer treated with first-line platinum-based chemotherapy. Ann Oncol 2012;23:2931–6.
14. 14. Bang YJ. Treatment of ALK-positive non-small cell lung cancer. Arch Pathol Lab Med 2012;136:1201–4.
15. 15. Vijayvergia N, Mehra R. Clinical challenges in targeting anaplastic lymphoma kinase in advanced non-small cell lung cancer. Cancer Chemother Pharmacol 2014;74:437–46.
16. 16. Rolfo C, Passiglia F, Castiglia M, Raez LE, Germonpre P, Gil-Bazo I, et al. ALK and crizotinib: after the honeymoon…what else? Resistance mechanisms and new therapies to overcome it. Transl Lung Cancer Res 2014;3:250–61.
17. 17. Gridelli C, Peters S, Sgambato A, Casaluce F, Adjei AA, Ciardiello F. ALK inhibitors in the treatment of advanced NSCLC. Cancer Treat Rev 2014;40:300–6.
18. 18. Ou SH, Kwak EL, Siwak-Tapp C, Dy J, Bergethon K, Clark JW, et al. Activity of crizotinib (PF02341066), a dual mesenchymalepithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol 2011;6(5):942–6.
19. 19. Solomon BJ, Mok T. First-line crizotinib in ALK-positive lung cancer. N Engl J Med 2015;372(8):782.
20. 20. Forde PM, Rudin CM. Crizotinib in the treatment of non-smallcell lung cancer. Expert Opin Pharmacother 2012;13(8):1195– 201.
21. 21. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012;4(120):120ra17.
22. 22. Wu J, Savooji J, Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol 2016;9:19.
23. 23. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012;18(5):1472–82.
24. 24. Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, et al. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. J Clin Oncol 2015;33(17):1881–8.
25. 25. Song Z, Wang M, Zhang A. Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance. Acta Pharm Sin B 2015;5(1):34–7.
26. 26. Sassier M, Mennecier B, Gschwend A, Rein M, Coquerel A, Humbert X, et al. Successful treatment with ceritinib after crizotinib induced hepatitis. Lung Cancer 2016;95:15–6.
27. 27. Ou SH, Milliken JC, Azada MC, Miller VA, Ali SM, Klempner SJ. ALK F1174V mutation confers sensitivity while ALK I1171 mutation confers resistance to alectinib. The importance of serial biopsy post progression. Lung Cancer 2016;91:70–2.
28. 28. Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)- N4-(2(isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (LDK378)currently in phase 1 and phase 2 clinical trials. J Med Chem 2013;56(14):5675–90.
29. 29. Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 2014;4(6):662–73.
30. 30. Rothschild S. New treatment options for ALK+ advanced nonsmall-cell lung cancer: critical appraisal of ceritinib. Ther Clin Risk Manag 2016;12:735–41.
31. 31. Rossi A. Alectinib for ALK-positive non-small-cell lung cancer. Expert Rev Clin Pharmacol 2016;9(8):1005–13.
32. 32. Zou HY, Friboulet L, Kodack DP, Engstrom LD, Li Q, West M, et al. PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. Cancer Cell 2015;28(1):70–81.
33. 33. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:4247–53.
34. 34. McCoach CE, Bivona TG, Blakely CM, Doebele RC. Neoadjuvant Oncogene-Targeted Therapy in Early Stage Non-Small-Cell Lung Cancer as a Strategy to Improve Clinical Outcome and Identify Early Mechanisms of Resistance. Clin Lung Cancer 2016;17(5):466–69.