T790米
奥西默替尼
表皮生长因子受体
癌症研究
肺癌
生物
医学
PI3K/AKT/mTOR通路
癌症
肝细胞生长因子受体
肿瘤科
埃罗替尼
吉非替尼
肝细胞生长因子
内科学
信号转导
受体
C-Met公司
细胞生物学
作者
Jingyi He,Zhengrong Huang,Linzhi Han,Yan Gong,Conghua Xie
标识
DOI:10.3892/ijo.2021.5270
摘要
Targeted therapy with epidermal growth factor receptor (EGFR)‑tyrosine kinase inhibitors (TKIs) is a standard modality of the 1st‑line treatments for patients with advanced EGFR‑mutated non‑small cell lung cancer (NSCLC), and substantially improves their prognosis. However, EGFR T790M mutation is the primary mechanism of 1st‑ and 2nd‑generation EGFR‑TKI resistance. Osimertinib is a representative of the 3rd‑generation EGFR‑TKIs that target T790M mutation, and has satisfactory efficacy in the treatment of T790M‑positive NSCLC with disease progression following use of 1st‑ or 2nd‑generation EGFR‑TKIs. Other 3rd‑generation EGFR‑TKIs, such as abivertinib, rociletinib, nazartinib, olmutinib and alflutinib, are also at various stages of development. However, the occurrence of acquired resistance is inevitable, and the mechanisms of 3rd‑generation EGFR‑TKI resistance are complex and incompletely understood. Genomic studies in tissue and liquid biopsies of resistant patients reveal multiple candidate pathways. The present review summarizes the recent findings in mechanisms of resistance to 3rd‑generation EGFR‑TKIs in advanced NSCLC, and provides possible strategies to overcome this resistance. The mechanisms of acquired resistance mainly include an altered EGFR signaling pathway (EGFR tertiary mutations and amplification), activation of aberrant bypassing pathways (hepatocyte growth factor receptor amplification, human epidermal growth factor receptor 2 amplification and aberrant insulin‑like growth factor 1 receptor activation), downstream pathway activation (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) and histological/phenotypic transformations (SCLC transformation and epithelial‑mesenchymal transition). The combination of targeted therapies is a promising strategy to treat osimertinib‑resistant patients, and multiple clinical studies on novel combined therapies are ongoing.
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