奥希替尼治疗非小细胞肺癌患者的耐药机制研究进展

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摘要奥希替尼是第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）。目前被批准用于EGFR突变晚期非小细胞肺癌（NSCLC）患者的一线治疗及第一代EGFR-TKIs治疗进展后伴有T790M突变NSCLC的二线治疗。临床研究显示，奥希替尼能够明显改善NSCLC患者的无进展生存期（PFS），但同时也带来了严重的耐药问题。近年来研究发现，一线应用奥希替尼的耐药机制主要有依赖EGFR通路、旁路信号通路的激活；二线及二线后应用奥希替尼所产生的耐药机制有依赖EGFR通路、旁路信号通路的激活，细胞表型转化。不同的用药时间产生的耐药机制有所不同。本文将从临床用药时间角度对奥希替尼耐药机制及治疗策略进行综述，以期为防治或延缓奥希替尼耐药提供理论依据。

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	王会宜康小红

关键词 ：非小细胞肺癌, 奥希替尼, 耐药

Abstract：Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). It is currently approved for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutation and second-line treatment with T790M mutant NSCLC after the first-generation EGFR-TKIs treatment progresses. Clinical studies have shown that Osimertinib can significantly improve the progression-free survival (PFS) of NSCLC patients, but it also brings serious drug resistance problems. In recent years, studies have found that the first-line application of Osimertinib resistance mechanism mainly depends on the activation of EGFR pathway and bypass signaling pathway; the drug resistance mechanism produced by the second-line and second-line application of Osimertinib depends on the activation of the EGFR pathway, the bypass signaling pathway, and the transformation of the cell phenotype. Osimertinib has different drug resistance mechanisms at different times. In order to provide a theoretical basis for the prevention and treatment of Osimertinib resistance, this article will review the different drug resistance mechanisms and treatment strategies of Osimertinib from the perspective of clinical drug use time.

Key words： Non-small-cell-lung cancer Osimertinib Resistance

基金资助:国家自然科学基金资助项目（81874392）。

通讯作者: 康小红（1978.3-），女，博士，副主任医师，硕士生导师；研究方向：恶性肿瘤综合治疗，主要是呼吸系统和消化系统肿瘤。

作者简介: 王会宜（1991.11-），女，新乡医学院第一临床学院2017级肿瘤学专业在读硕士研究生；研究方向：肺癌靶向药物耐药机制。

引用本文:

王会宜康小红. 奥希替尼治疗非小细胞肺癌患者的耐药机制研究进展[J]. 中国医药导报, 2020, 17(28): 32-35.
WANG Huiyi KANG Xiaohong. Research progress on the drug resistance mechanism of Osimertinib in patients with non-small cell lung cancer. 中国医药导报, 2020, 17(28): 32-35.

链接本文:

http://www.yiyaodaobao.com.cn/CN/ 或 http://www.yiyaodaobao.com.cn/CN/Y2020/V17/I28/32

[1] Akamatsu H，Katakami N，Okamoto I，et al. Osimertinib in Japanese patients with EGFR T790M mutation-positive advanced non-small-cell lung cancer：AURA3 trial [J]. Cancer Sci，2018，109（6）：1930-1938.
[2] Cho BC，Chewaskulyong B，Lee KH，et al. Osimertinib versus Standard of Care EGFR TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC：FLAURA Asian Subset [J]. J Thorac Oncol，2019，14（1）：99-106.
[3] Jean BA，Maurice P，David P，et al. Real-life efficacy of Osimertinib in pretreated patients with advanced non-small cell lung cancer harboring EGFR T790M mutation [J]. Lung Can，2019，127：96-102.
[4] Cho BC，Cheng Y，Zhou C，et al. Mechanisms of acquired resistance to first-line Osimertinib：preliminary data from the phase Ⅲ FLAURA study [J]. Ann Oncol，2018，29（suppl 8）：viii740.
[5] Uchibori K，Inase N，Nishio M，et al. Identification of Mutation Accumulation as Resistance Mechanism Emerging in First-Line Osimertinib Treatment [J]. J Thorac Oncol，2018，13（7）：915-925.
[6] Niederst MJ，Hu H，Mulvey HE，et al. The allelic context of the C797S mutation acquired upon treatment with third generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies [J]. Clin Cancer Res，2015，21：3924-3933.
[7] Minari R，Bordi P，La Monica S，et al. Concurrent Acquired BRAF V600E Mutation and MET Amplification as Resistance Mechanism of First-Line Osimertinib Treatment in a Patient with EGFR-Mutated NSCLC [J]. J Thorac Oncol，2018，13：e89-e91.
[8] Oxnard GR，Hu Y，Mileham KF，et al. Assessment of Resistance Mechanisms and Clinical Implications in Patients with EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib [J]. JAMA Oncol，2018，4（11）：1527-1534.
[9] Thress KS，Paweletz CP，Felip E，et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M [J]. Nat Med，2015，21（6）：560-562.
[10] Piotrowska Z，Nagy R，Fairclough S，et al. OA 09.01 Characterizing the Genomic Landscape of EGFR C797S in Lung Cancer Using ctDNA Next-Generation Sequencing [J]. J Thorac Oncol，2017，12（11）：S1767.
[11] Arulananda S，Do H，Musafer A，et al. Combination Osimertinib and Gefitinib in C797S and T790M EGFR-Mutated Non-Small Cell Lung Cancer [J]. J Thorac Oncol，2017，12（11）：1728-1732.
[12] Wang Z，Yang JJ，Huang J，et al. Brief Report：Lung adenocarcinoma harboring，EGFR，T790M and， in trans，C797S responds to combination therapy of first and third generation EGFR-TKIs and shifts allelic configuration at resistance [J]. J Thorac Oncol，2017，12：1723-1727.
[13] Chia PL，Do H，Morey A，et al. Temporal changes of EGFR mutations and T790M levels in tumor and plasma DNA following AZD9291 treatment [J]. Lung Can，2016，98：29-32.
[14] Lin CC，Shih JY，Yu CJ，et al. Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with Osimertinib：a genomic study [J]. Lancet Respir Med，2018，6（2）：107-116.
[15] Planchard D，Loriot Y，André F，et al. EGFR independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients [J]. Ann Oncol，2015，26（10）：2073-2078.
[16] Ou SI，Agarwal N，Ali SM. High MET amplification level as a resistance mechanism to Osimertinib （AZD9291） in a patient that symptomatically responded to crizotinib treatment post-Osimertinib progression [J]. Lung Can，2016，98：59-61.
[17] La Monica S，Cretella D，Bonelli M，et al. Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI Osimertinib in NSCLC EGFR mutated cell lines [J]. J Exp Clin Cancer Res，2017，36（1）：174.
[18] Ortiz-Cuaran S，Scheffler M，Plenker D，et al. Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors [J]. Clin Cancer Res，2016，22（19）：4837-4847.
[19] Ramalingam SS，Yang CH，Lee CK，et al. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer [J]. J Clin Oncol，2018，36（9）：841-849.
[20] Oxnard GR，Thress K，Paweletz C，et al. Mechanisms of Acquired Resistance to AZD9291 in EGFR T790M Positive Lung Cancer [J]. J Thorac Oncol，2015，10（9）：S207.
[21] Chabon JJ，Simmons AD，Lovejoy AF，et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients [J]. Nat Commun，2016，7：11815.
[22] Dong C，Yang R，LI H，et al. Econazole nitrate inhibits PI3K activity and promotes apoptosis in lung cancer cells [J]. Sci Rep，2017，7（1）：17987.
[23] Eberlein CA，Stetson D，Markovets AA，et al. Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models [J]. Cancer Res，2015，75（12）：2489-2500.
[24] Ho CC，Liao WY，Lin CA，et al. Acquired BRAF V600E Mutation as Resistant Mechanism after Treatment with Osimertinib [J]. J Thorac Oncol，2017，12（3）：567-572.
[25] Ohashi K，Sequist LV，Arcila ME，et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS，NRAS，or MEK1 [J]. Proc Natl Acad Sci USA，2012，109（31）：E2127-E2133.
[26] Lee JK，Lee J，Kim S，et al. Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas [J]. J Clin Oncol，2017，35（26）：3065-3074.
[27] Taniguchi Y，Horiuchi H，Morikawa T. Small-Cell Carcinoma Transformation of Pulmonary Adenocarcinoma after Osimertinib Treatment：A Case Report [J]. Case Rep Oncol，2018，11（2）：323-329.
[28] Ham JS，Kim S，Kim HK，et al. Two Cases of Small Cell Lung Cancer Transformation from EGFR Mutant Adenocarcinoma During AZD9291 Treatment [J]. J Thorac Oncol，2016，11（1）：e1-e4.
[29] Poh ME，Liam CK，Rajadurai P. Epithelial-to-mesenchymal transition （EMT） causing acquired resistance to afatinib in a patient with epidermal growth factor receptor mutant lung adenocarcinoma [J]. J Thorac Dis，2018，10 （7）：E560-E563.
[30] Sakuma Y，Nishikiori H，Hirai S，et al. Prolyl isomerase Pin1 promotes survival in EGFR mutant lung adenocarcinoma cells with an epithelial-mesenchymal transition phenotype [J]. Lab Invest，2016，96（4）：391-398.