Metformin sensitizes AML cells to venetoclax through endoplasmic reticulum stress—CHOP pathway

Summary Venetoclax inhibits acute myeloid leukaemia by inhibiting BCL‐2 targeting, and a combination regimen with venetoclax has been explored. Although these regimens produce better clinical results, the vast majority of patients still suffer from disease recurrence or primary drug resistance. Metformin has been demonstrated to induce apoptosis in cancer cells. However, whether it can synergize with venetoclax and the underlying mechanisms of metformin‐induced apoptosis are not fully understood. In this study, we investigated the effect of metformin and venetoclax on the growth of AML cells in vitro and in vivo. In both Molm13 and THP‐1 cell lines, metformin and venetoclax synergistically inhibited the proliferation and induced apoptosis of leukaemia cells. Most importantly, the combination of metformin and venetoclax treatment significantly increased the expression levels of the endoplasmic reticulum (ER) stress‐related marker CHOP, for example, in AML cell lines. Knockdown of CHOP markedly attenuated the metformin‐ and venetoclax‐induced cell apoptosis. Moreover, the combination of metformin and venetoclax demonstrated prominent anti‐leukaemia effects in xenograft models and bone marrow samples from AML patients. In summary, the combination of metformin and venetoclax showed enhanced anti‐leukaemia activity with acceptable safety in AML patients, representing a new combinatorial strategy worth further clinical investigation to treat AML. Metformin and venetoclax combination induces apoptosis through enhancing endoplasmic reticulum stress. The combination of metformin and venetoclax triggers the proximal ER stress sensors, leading to CHOP induction and nuclear translocation, which further regulates the expression of apoptosis‐related genes and triggers apoptosis. Knockdown of CHOP partially ameliorates the anti‐leukemic effects of the combination of metformin and venetoclax.