Therapeutic potential of the novel Bcl-2/Bcl-X L dual inhibitor, APG1252, alone or in combination against non-small cell lung cancer.
Luxi QianKarin A VallegaWeilong YaoDongsheng WangYifan ZhaiXia HeShi-Yong SunPublished in: Molecular carcinogenesis (2022)
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.
Keyphrases
- epidermal growth factor receptor
- induced apoptosis
- small cell lung cancer
- advanced non small cell lung cancer
- endoplasmic reticulum stress
- cell cycle arrest
- oxidative stress
- signaling pathway
- tyrosine kinase
- cell death
- pi k akt
- brain metastases
- single cell
- cell therapy
- stem cells
- cell proliferation
- induced pluripotent stem cells
- wild type
- lymph node metastasis