Overcoming acquired resistance to third-generation EGFR inhibitors by targeting activation of intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation, or both.
Overcoming acquired resistance to third-generation EGFR inhibitors by targeting activation of intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation, or both.
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DOI：
10.1038/s41388-022-02200-5
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发表时间：
2022-03
期刊：
影响因子：
8
通讯作者：
Sun SY
中科院分区：
文献类型：
--
作者：
Ma G;Deng Y;Qian L;Vallega KA;Zhang G;Deng X;Owonikoko TK;Ramalingam SS;Fang DD;Zhai Y;Sun SY
使用突变选择性第三代EGFR-酪氨酸激酶抑制剂（EGFR-TKI）（如奥希替尼）治疗EGFR突变型非小细胞肺癌（NSCLC）已在临床上取得显著成功。然而，直接的挑战是获得性耐药的出现，限制了患者的长期缓解。这项研究提出了一种新的策略，通过直接靶向内在凋亡途径来克服对奥希替尼和其他第三代EGFR-TKI的获得性耐药性。我们发现，奥希替尼与Mcl-1抑制或Bax激活联合使用时，协同降低了不同奥希替尼耐药细胞系的存活率，增强了内源性凋亡的诱导，并抑制了体内奥希替尼耐药肿瘤的生长。有趣的是，奥希替尼与Mcl-1抑制和Bax激活的三重组合在降低奥希替尼抗性细胞的存活和诱导凋亡以及抑制奥希替尼抗性肿瘤的生长方面表现出最有效的活性。这些影响与增加的内在凋亡途径的激活增强线粒体细胞色素C和Smac释放证明。因此，本研究令人信服地证明了一种通过Mcl-1抑制、Bax激活或两者靶向激活内源性凋亡途径克服对奥希替尼和其他第3代EGFR-TKI获得性耐药的新策略，从而进一步验证了该策略的临床有效性。
Treatment of EGFR-mutant non-small cell lung cancer (NSCLC) with mutation-selective third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib has achieved remarkable success in the clinic. However, the immediate challenge is the emergence of acquired resistance, limiting the long-term remission of patients. This study suggests a novel strategy to overcome acquired resistance to osimertinib and other third generation EGFR-TKIs through directly targeting the intrinsic apoptotic pathway. We found that osimertinib, when combined with Mcl-1 inhibition or Bax activation, synergistically decreased the survival of different osimertinib-resistant cell lines, enhanced the induction of intrinsic apoptosis, and inhibited the growth of osimertinib-resistant tumor in vivo. Interestingly, the triple- combination of osimertinib with Mcl-1 inhibition and Bax activation exhibited the most potent activity in decreasing the survival and inducing apoptosis of osimertinib-resistant cells and in suppressing the growth of osimertinib-resistant tumors. These effects were associated with increased activation of the intrinsic apoptotic pathway evidenced by augmented mitochondrial cytochrome C and Smac release. Hence, this study convincingly demonstrates a novel strategy for overcoming acquired resistance to osimertinib and other 3rd generation EGFR-TKIs by targeting activation of the intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation or both, warranting further clinical validation of this strategy.
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