The Third-Generation EGFR Inhibitor, Osimertinib, Promotes c-FLIP Degradation, Enhancing Apoptosis Including TRAI-Induced Apoptosis in NSCL Cells with Activating EGFR Mutations
The Third-Generation EGFR Inhibitor, Osimertinib, Promotes c-FLIP Degradation, Enhancing Apoptosis Including TRAI-Induced Apoptosis in NSCL Cells with Activating EGFR Mutations
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第三代 EGFR 抑制剂奥希替尼促进 c-FLIP 降解，增强细胞凋亡，包括激活 EGFR 突变的 NSCLC 细胞中 TRAIL 诱导的细胞凋亡
DOI：
10.1016/j.tranon.2019.02.006
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发表时间：
2019-05-01
影响因子：
5
通讯作者：
Sun, Shi-Yong
中科院分区：
文献类型：
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作者：
Shi, Puyu;Zhang, Shuo;Sun, Shi-Yong
第三代EGFR抑制剂奥西替尼（AZD9291）选择性和不可逆地抑制EGFR激活和t790m突变体，同时保留野生型EGFR。奥西替尼现已被批准用于EGFR突变激活的非小细胞肺癌（NSCLC）患者（一线）或通过t790m突变对第一代EGFR抑制剂产生耐药性的患者（二线）。不幸的是，所有患者最终都会复发并对奥西替尼产生耐药性。因此，为了提高奥西替尼的治疗效果和克服耐药性，有必要充分了解奥西替尼耐药发展的生物学基础。细胞flice抑制蛋白（c-FLIP）是caspase-8的截断形式，是外源性凋亡途径的关键抑制剂。目前的研究表明，奥西替尼通过促进其降解来降低c-FLIP水平，并增强主要在EGFR突变激活的NSCLC中由肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的细胞凋亡。此外，c-FLIP表达水平的调节在一定程度上也改变了EGFR突变体NSCLC细胞发生奥西替尼诱导的凋亡的敏感性，提示c-FLIP抑制是奥西替尼对EGFR突变体NSCLC抗肿瘤活性的重要事件。
The third-generation EGFR inhibitor, osimertinib (AZD9291), selectively and irreversibly inhibits EGFR activating and T790 M mutants while sparing wild-type EGFR. Osimertinib is now an approved drug for non-small cell lung cancer (NSCLC) patients with activating EGFR mutations (first-line) or those who have become resistant to 1st generation EGFR inhibitors through the T790 M mutation (second-line). Unfortunately, all patients eventually relapse and develop resistance to osimertinib. Hence, it is essential to fully understand the biology underlying the development of resistance to osimertinib in order to improve its therapeutic efficacy and overcome resistance. Cellular FLICE-inhibitory protein (c-FLIP) is a truncated form of caspase-8 and functions as a key inhibitor of the extrinsic apoptotic pathway. The current study has demonstrated that osimertinib reduces c-FLIP levels via facilitating its degradation and enhances apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) primarily in NSCLC with activating EGFR mutations. Moreover, modulation of c-FLIP expression levels, to some degree, also alters the sensitivities of EGFR mutant NSCLC cells to undergo osimertinib-induced apoptosis, suggesting that c-FLIP suppression is an important event contributing to the antitumor activity of osimertinib against EGFR mutant NSCLC.