肺腺癌驱动基因的临床研究与进展

摘要/Abstract

摘要： 肺癌(lung cancer)是全球死亡率最高的恶性肿瘤之一,严重危害人类的健康。目前,肺癌,尤其是肺腺癌的发生发展与诸多驱动基因之间的关系都已受到了众多学者的认可。随着细胞信号传导通路研究的深入,近几年出现了大量针对信号传导通路中不同靶点的靶向治疗药物。本文总结现有相关临床研究,综述多种驱动基因在肺腺癌发生发展过程中的作用机制。同时,汇总基于有效分子标记物的前瞻性临床试验,来评估多种分子靶向药物的疗效,并对未来的靶向治疗做出展望。

关键词: 驱动基因, 肺癌, 靶向治疗

Abstract: Lung cancer is one of the most common malignant tumors worldwide, which seriously harm human health. Nowadays, the causal relationship between the development of lung cancer, especially lung adenocarcinoma, and many driver genes, have been accepted by quite a lot of scholars. In recent years, with further research on cell signal pathways, a rising number of drugs have emerged, targeting different signaling pathways. In this article, we carried out a summary of relevant clinical research, in order to outline the mechanisms of a variety of driver genes in lung adenocarcinoma. Besides, we sum up prospective clinical trials of effective molecular markers, to assess the curative effects of several molecular-targeted drugs. And finally, we give an outlook of future targeted therapies.

Key words: driver gene, lung cancer, targeted therapy

中图分类号:

R734.2

赵毅超, 张丽琴. 肺腺癌驱动基因的临床研究与进展[J]. 中国临床药理学与治疗学, 2015, 20(1): 112-117.

ZHAO Yi-chao, ZHANG Li-qin. Clinical research and progress of the driver genes of lung adenocarcinoma[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(1): 112-117.

参考文献

[1] Jemal A, Bray F, Center MM, et al. Global cancer statistics[J]. CA Cancer J Clin, 2011, 61(2): 69-90.
[2] Burgess DJ. Cancer genetics: Initially complex, always heterogeneous[J]. Nat Rev Cancer, 2011, 11(3): 153.
[3] Hoelder S, Clarke PA, Workman P. Discovery of small molecule cancer drugs: Successes, challenges and opportunities[J]. Mol Oncol, 2012, 6(2): 155-176.
[4] Red Brewer M,Choi SH,Alvarado D,et al. The juxtamembrane region of the EGF receptor functions as an activation domain[J].Molcel,2009,34(6):641-651.
[5] Gazdar AF, Minna JD. Deregulated EGFR signaling during lung cancerprogression: Mutations, amplicons, and autocrine loops[J]. Cancer Prev Res(Phila), 2008, 1(3): 156-160.
[6] Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer:the evolving role of individualized therapy[J].Cancer Metastasis Rev,2010,29(1):37-48.
[7] Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer[J]. Nat Rev Cancer, 2007, 7(3): 169-181.
[8] Mok TS, Wu YL, Thongprasert S, et al.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma[J]. N Engl J Med,2009,361(10):947-957.
[9] Pan W, Miller V, Zakowski M, et al.EGF receptor gene mutations are common in lung cancers from “never smokers”and are associated with sensitivity of tumors to gefitinib and erlotinib[J].Proc Natl Acad Sci USA,2004,101(36):13306-13311.
[10] Mok TS, Wu YL, Thongprasert S,et al.Gefitinib or carboplatin-pa-elitaxel in pulmonary adenocareinoma[J].N Engl J Med,2009,361(10):947-957.
[11] Maemondo M,Inoue A,Kobayashi K, et al.Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR[J].N Engl J Med, 2010,362(25):2380-2388.
[12] Mok TS. Personalized medicine in lung cancer: What we need to know [J]. Nat Rev Clin Oncol, 2011, 8(11): 661-668.
[13] 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[J]. Lancet Oncol,2010,11(2):121-128.
[14] Spector NL, Blackwell KL. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor2-positive breast cancer[J].J Clin Oncol,2009,27 (34):5838-5847.
[15] Arcila ME, Chaf JE, Nafa K, et a1. Prevalence clinicopathologic associations and molecular spectrum of ERBB2(HER2) tyrosine kinase mutations in lung adenocarcin0mas[J].Clin Cancer Res,2012,18(18):4910-4918.
[16] Cappuzzo F, Varella Garcia M, Shigenmtsu H, et al.Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor.positive non-small-cell lung cancer patients[J].J Clin Oncol,2005,23(22):5007-5018.
[17] Zinner RG, Glisson BS, Fossella FV,et al.Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overex-pressing,untreated,advanced non-small cell lung cancer:report of a phaseII trial and findings regarding optimal identification of patients with Her2-overexpressing disease[J].Lung Cancer,2004,44(1):99-110.
[18] Messersmith WA,Ahnen DJ.Targeting EGFR in colorec-tat cancer[J].N Engl J Med,2008,359(17):1834-1836.
[19] Lam WK. Lung cancer in Asian women-the environment and genes[J].Respirology,2005,10(4):408-417.
[20] McLeod C,Bagust A,Boland A,et al.Erlotinib for the treatment of relapsed non-small eell lung cancer[J].Health Tectmol Assess, 2009, 6(13):41-47.
[21] Soda M, Choi YL,Enomoto M, et al.Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer[J].Nature,2007,448(7153):56-66.
[22] Takahashi T, Sonobe M, Kobayashi M,et al.Clinicopathologic features of non-small-cell lung cancer with EML4-AI K fusion gene[J].Ann Surg Oncol,2010,17(3):889.
[23] Sasaki T, Rodig SJ, Chirieac LR,et al.The biology and treatment of EMIA-ALK non-small-cell lung cancer[J].Eur J Cancer,2010,46(10):1773.
[24] Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK lung cancers are characterized by rare other mutations,arrF-1 cell lineage,an acinar histology,and young onset[J].Mod Pathol,2009,22(4):508-515.
[25] Sasaki T, Rodig SJ, Chirieac LR,et al.The biology and treatment of EMIA-ALK non-small celllung cancer[J].Eur J Cancer,2010,46(10):1773-1780.
[26] Jin G, Jeon HS, Lee EB,et al.EMI4-ALK fusion gene in Korean non-small cell lung cancer[J].J Korean Med Sci, 2012, 27(2):228-30.
[27] Camidge DR, Bang Y, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study[J]. Lancet Oncol,2012,13(10):1011-1019.
[28] Kohno T, Ichikawa H, Totoki Y,et al.KIF5B,RET fllsions in lung adenocarcinomal [J].Nat Med,2012,18(3):375-377.
[29] Wang R, Hu H, Pan Y, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer[J]. J Clin Oncol,2012,30(35): 4352-4359.
[30] Banner AE, Lemon WJ, Devereux TR, et al. Molecular profiling of mouse lung tumors:association with tumor progression, lung development, and human lung adenocarcinomas[J]. Oncogene,2004,23(5):1166-1176.
[31] Bergethon K, Shaw AT, Ou SH, et al.ROSI rearrangements define a unique molecular class oflung cancers[J].J Clin Oncol,2012,30(8):863-870.
[32] Ou SH,Tan J,Yen Y,et al.ROS1 as a druggable receptor tyrosine kinase:lessons learned from inhibiting the ALK pathway[J].Expert Rev Anticaneer Ther,2012,12(4):447-456.
[33] Shaw AT, Yeap BY, Solomon BJ,et al.Effect of crizotinib on overall survival in patients with advanced non-small cel1 lung cancer harbouring ALK gene rearrangement: a retrospective analysis[J].Lancet Oncol, 2011,12(11):1004-1012.
[34] Ikawa S, Fukui M, Ueyama Y, et al. B-raf, a new member of the raf family, is activated by DNA rearrangement[J]. Mol Cell Biol, 1988, 8(6): 2651-2654.
[35] Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer[J]. Nature, 2002, 417(6892): 949-954.
[36] Pao W, Girard N. New driver mutations in non-small-cell lung cancer[J]. Lancet Oncol, 2011, 12(2): 175-180.
[37] Yang H, Higgins B, Kolinsky K, et al. RG7204 (PLX4032), a selective BRAF V600E inhibitor, displays potent antitumor activity in preclinical melanoma models[J]. Cancer Res, 2010, 70(13): 5518-5527.
[38] Lee JT, Li L, Brafford PA, et al. PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas[J]. Pigment Cell Melanoma Res, 2010, 23(6): 820-827.
[39] Livingstone E, Zimmer L, Piel S, et al. PLX4032: does it keep its promise for metastatic melanoma treatment[J] ? Expert Opin Investig Drugs, 2010, 19(11):1439-1449.