非小细胞肺癌第三代表皮生长因子受体-酪氨酸激酶抑制剂的耐药机制及治疗策略

doi:10.3969/j.issn.1674-8115.2022.04.017

摘要/Abstract

摘要：

表皮生长因子受体（epidermal growth factor receptor，EGFR）基因是非小细胞肺癌最常见的驱动基因。针对EGFR突变的酪氨酸激酶抑制剂（tyrosine kinase inhibitors，TKIs）是EGFR突变患者的一线治疗首选方案。虽然第一、二、三代TKIs已经广泛应用于临床，但无法避免的继发耐药和部分初治患者的原发耐药，仍旧给长线用药带来了巨大挑战。一代以及二代EGFR-TKIs的耐药机制研究较为清楚，包括T790M突变、MET扩增、ERBB2扩增、IGF1R上调、AXL活化等。第三代TKIs可克服前2代最常见的T790M突变，但是随其在临床应用的日益广泛，耐药问题正引起广泛的重视，相关机制和治疗策略目前仍在研究中。机制分为EGFR依赖性和非依赖性2种，包括靶基因突变、旁路信号通路激活、表型转化、表观遗传调控以及免疫抑制微环境等。第四代TKIs、联合治疗以及免疫治疗等都是潜在的耐药后治疗方式。

关键词: 非小细胞肺癌, 表皮生长因子受体, 蛋白激酶抑制剂, 耐药性

Abstract:

Epidermal growth factor receptor (EGFR) gene is the most common driver gene of non-small cell lung cancer. Tyrosine kinase inhibitors (TKIs) targeting EGFR mutations are the first-line treatment choice for patients with EGFR mutations. Although three generations of drugs have been widely used in clinical practice, unavoidable secondary resistance and primary resistance to some treatment-naive patients still pose great challenges to the long-term use of EGFR-TKIs. Resistance mechanism of the first- and second-generation EGFR-TKIs are well studied, including T790M mutation, MET amplification, ERBB2 amplification, IGF1R up-regulation, AXL activation, etc. The third-generation TKIs can overcome the most common T790M mutation that the first two generations bring in, but with the increasingly widespread clinical use, their drug resistance problem is also attracting widespread attention, and the related mechanisms and overcoming strategies are still under study. Mechanisms can be divided into EGFR-dependent and EGFR-independent ones, involving target-gene mutation, bypass signaling activation, phenotypic plasticity, epigenetic regulation, inhibitory immune microenvironment and so on. The fourth-generation TKIs, combination therapy and immunotherapy are all potential modalities after drug resistance.

Key words: non-small cell lung cancer, epidermal growth factor receptor (EGFR), protein kinase inhibitor, drug resistance

中图分类号:

R734.2

陆文清, 孟周文理, 虞永峰, 陆舜. 非小细胞肺癌第三代表皮生长因子受体-酪氨酸激酶抑制剂的耐药机制及治疗策略[J]. 上海交通大学学报（医学版）, 2022, 42(4): 535-544.

LU Wenqing, MENG Zhouwenli, YU Yongfeng, LU Shun. Resistance mechanisms and overcoming strategies of the third-generation EGFR-TKI in non-small cell lung cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(4): 535-544.

图/表 1

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