Mechanisms of osimertinib resistance and emerging treatment options
Mechanisms of osimertinib resistance and emerging treatment options
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DOI：
10.1016/j.lungcan.2020.07.014
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发表时间：
2020-09-01
期刊：
影响因子：
5.3
通讯作者：
Leighl, Natasha B.
中科院分区：
文献类型：
--
作者：
Schmid, Sabine;Li, Janice J. N.;Leighl, Natasha B.
奥希替尼是一种不可逆的EGFR酪氨酸激酶抑制剂，最初获批用于治疗表现出T790 M耐药突变的EGFR阳性患者的二线治疗，现在已成为所有EGFR阳性患者的新标准治疗，作为一线治疗。尽管奥希替尼有效，但仍不可避免地产生耐药性，耐药机制可大致分为两类：靶向EGFR依赖性机制和脱靶EGFR非依赖性机制。EGFR依赖性耐药通常与通过变构/构象转变改变结合位点破坏奥希替尼结合的额外EGFR突变相关; EGFR非依赖性机制主要与替代途径激活或异常下游信号传导相关，但也与导致小细胞转化的谱系可塑性相关。MET扩增是奥希替尼治疗耐药的最常见脱靶机制，最近发表的早期试验显示，在发生耐药后，MET抑制剂与奥希替尼联合使用具有前景的结果。本综述将总结总体和不同治疗环境中的耐药机制，并将重点关注奥希替尼失败后针对特定获得性改变的潜在新治疗选择。
Osimertinib is an irreversible EGFR-tyrosine kinase inhibitor initially approved for treatment of EGFR-positive patients exhibiting a T790 M resistance mutation in the second line setting and now emerging as the new standard of care for all EGFR positive patients as first-line treatment. Despite its efficacy, resistance to osimertinib inevitably develops and mechanisms of resistance can be grouped broadly in two categories: on-target EGFR-dependent and off-target EGFR-independent mechanisms. EGFR-dependent resistance typically is associated with additional EGFR-mutations disrupting the osimertinib binding through changes in the binding site by allosteric/ conformational transitions; EGFR-independent mechanisms are related mostly to alternate pathway activation or aberrant downstream signalling but also to lineage plasticity leading to small cell transformation. MET amplification is the most frequent off-target mechanisms of resistance to osimertinib treatment and recently published early trials show promising results for combination of MET-inhibitors with osimertinib upon development of resistance. This review will summarize mechanisms of resistance overall and in different treatment settings and will focus on potential new treatment options targeting specific acquired alterations after osimertinib failure.