Aspirin sensitizes osimertinib-resistant NSCLC cells in vitro and in vivo via Bim-dependent apoptosis induction
Aspirin sensitizes osimertinib-resistant NSCLC cells in vitro and in vivo via Bim-dependent apoptosis induction
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阿司匹林通过 Bim 依赖性细胞凋亡诱导在体外和体内使奥希替尼耐药的 NSCLC 细胞变得敏感。
DOI：
10.1002/1878-0261.12682
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发表时间：
2020-05-05
影响因子：
6.6
通讯作者：
He Yong
中科院分区：
文献类型：
--
作者：
Han Rui;Hao Shuai;He Yong
奥希替尼是第三代不可逆表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），为EGFR激活突变患者提供了显著的临床获益。不幸的是，对于获得奥希替尼耐药的患者存在有限的治疗。我们观察到两名“特殊”患者在奥希替尼联合阿司匹林治疗后恢复了抗肿瘤反应。由于先前的数据表明阿司匹林在肿瘤细胞中诱导抗增殖作用，我们设计了一项临床前研究，以探索阿司匹林联合奥希替尼是否可以协同增敏奥希替尼耐药的非小细胞肺癌（NSCLC）细胞。在体外和体内研究了奥希替尼和阿司匹林联合治疗对奥希替尼耐药NSCLC细胞系的影响。奥希替尼和阿司匹林联合给药通过抑制Akt/FoxO 3a信号传导组分磷酸化和增加Bim表达，在奥希替尼耐药NSCLC细胞中诱导强烈的抗增殖和促凋亡作用。此外，通过siRNA敲低Bim显著减弱了阿司匹林对奥希替尼的再致敏。在体内，阿司匹林和奥希替尼的组合显著降低PC-9 GR 0 R细胞异种移植物的肿瘤生长。回顾性分析2015年1月至2019年1月在大坪医院接受奥希替尼治疗的NSCLC患者数据。根据45例NSCLC患者的临床数据，回顾性分析显示奥希替尼联合阿司匹林组的中位无进展生存期明显长于奥希替尼组。总之，阿司匹林通过促进Bim依赖性细胞凋亡，协同增强奥希替尼在奥希替尼耐药肺癌细胞中的抗肿瘤活性。这种联合治疗可能有效克服对奥希替尼的获得性耐药性，延长NSCLC患者的生存期。
Osimertinib, a third-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), provides marked clinical benefit for patients with EGFR-activating mutations. Unfortunately, limited treatments exist for patients who acquire osimertinib resistance. We observed two 'special' patients who regained an antitumor response with osimertinib plus aspirin treatment. As previous data indicate that aspirin induces antiproliferative effects in tumor cells, we designed a preclinical study to explore whether aspirin combined with osimertinib could synergistically sensitize osimertinib-resistant non-small-cell lung cancer (NSCLC) cells. The effects of combined treatment with osimertinib and aspirin on osimertinib-resistant NSCLC cell lines were examined in vitro and in vivo. The combination of osimertinib and aspirin induced strong antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cells through inhibition of Akt/FoxO3a signaling component phosphorylation and increased Bim expression. Furthermore, Bim knockdown by siRNA significantly attenuated osimertinib resensitization by aspirin. In vivo, combination of aspirin and osimertinib significantly decreased tumor growth of PC-9GROR cell xenografts. Data of patients with NSCLC who received osimertinib treatment at Daping Hospital between January 2015 and January 2019 were reviewed retrospectively. According to clinical data for 45 patients with NSCLC, retrospective analysis showed that the median progression-free survival was significantly longer in the osimertinib plus aspirin group than in the osimertinib group. In summary, aspirin synergistically enhances the antitumor activity of osimertinib in osimertinib-resistant lung cancer cells through promoting Bim-dependent apoptosis. This combination therapy may be effective in overcoming acquired resistance to osimertinib and prolonging survival in patients with NSCLC.