Targeting the induction of apoptosis is a promising cancer therapeutic strategy with some clinical success. This study focused on evaluating the therapeutic efficacy of the novel Bcl-2/Bcl-X_L dual inhibitor, APG1252-M1 (also named APG-1244; an in vivo active metabolite of APG1252 or pelcitoclax), as a single agent or in combination, against non-small cell lung cancer (NSCLC) cells. APG1252-M1 effectively decreased the survival of some NSCLC cell lines expressing low levels of Mcl-1 and induced apoptosis. Overexpression of ectopic Mcl-1 in the sensitive cells substantially compromised APG1252-M1's cell-killing effects, whereas inhibition of Mcl-1 greatly sensitized insensitive cell lines to APG1252-M1, indicating the critical role of Mcl-1 levels in impacting cell response to APG1252-M1. Moreover, APG1252-M1, when combined with the third generation epidermal growth factor receptor (EGFR) inhibitor, osimertinib, synergistically decreased the survival of EGFR-mutant NSCLC cell lines including those resistant to osimertinib with enhanced induction of apoptosis and abrogated emergence of acquired resistance to osimertinib. Importantly, the combination was effective in inhibiting the growth of osimertinib-resistant tumors in vivo. Collectively, these results demonstrate the efficacy of APG1252 alone or in combination against human NSCLC cells.

中文翻译：

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新型 Bcl-2/Bcl-XL 双重抑制剂 APG1252 单独或联合治疗非小细胞肺癌的治疗潜力

靶向细胞凋亡的诱导是一种有前途的癌症治疗策略，并取得了一些临床成功。本研究的重点是评估新型 Bcl-2/Bcl-X _{L的治疗效果}双重抑制剂，APG1252-M1（也称为 APG-1244；APG1252 或 pelcitoclax 的体内活性代谢物），作为单一药物或组合，对抗非小细胞肺癌 (NSCLC) 细胞。APG1252-M1 有效地降低了一些表达低水平 Mcl-1 的 NSCLC 细胞系的存活并诱导细胞凋亡。敏感细胞中异位 Mcl-1 的过度表达显着损害了 APG1252-M1 的细胞杀伤作用，而 Mcl-1 的抑制使不敏感的细胞系对 APG1252-M1 非常敏感，表明 Mcl-1 水平在影响细胞对 APG1252-M1 的反应中的关键作用APG1252-M1。此外，APG1252-M1 与第三代表皮生长因子受体 (EGFR) 抑制剂奥希替尼联合使用时，协同降低 EGFR 突变 NSCLC 细胞系的存活率，包括那些对奥希替尼耐药的细胞系，并增强细胞凋亡的诱导并消除对奥希替尼的获得性耐药性的出现。重要的是，该组合可有效抑制体内奥希替尼耐药肿瘤的生长。总的来说，这些结果证明了 APG1252 单独或组合对人类 NSCLC 细胞的功效。