Statin-induced mitochondrial priming sensitizes multiple myeloma cells to BCL2 and MCL1 inhibitors.

The BCL2 inhibitor venetoclax promotes apoptosis in blood cancer cells and is approved for treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, multiple myeloma (MM) cells are frequently more dependent on MCL-1 for survival, conferring resistance to venetoclax. Here we report that mevalonate pathway inhibition with statins can overcome resistance to venetoclax in MM cell lines and primary cells. Additionally, statins sensitize to apoptosis induced by MCL1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in MM, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize MM cells to venetoclax by upregulating two pro-apoptotic proteins: PUMA via a p53-independent mechanism, and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in MM.