MMCLs are sensitized to BH3 mimetics by simvastatin. We assessed a panel of seven myeloma cell lines including: OPM2, L363, KMS-12-PE, NCI-H929, MOLP8, RPMI-8226, and U266. A, Representative plots of statin-sensitive (black) MMCLs are shown alongside statin insensitive (red). The initial screen used PI exclusion to determine viability by flow cytometry. Rescue with 1 mmol/L mevalonate was demonstrated at the highest concentration of simvastatin to demonstrate on-target activity. Of note, statin-mediated killing of RPMI-8226 is not fully rescued by mevalonate, perhaps due to inefficient cellular uptake. n = 3, error bars indicate SD. B, IC50 of venetoclax or C, S63845 at concentrations of statins necessary to significantly shift the IC50. Significance (P value <0.05) was determined by extra sum-of-squares F test for differences in log IC50. Achieving significance was the classification determinant for statin-sensitive and statin-insensitive cell lines. *, P < 0.05; **, P < 0.01; *** , P < 0.001; ****, P < 0.0001 of Bonferroni-adjusted P values.
Funding
HHS | National Institutes of Health (NIH)
American Cancer Society (ACS)
Leukemia and Lymphoma Society (LLS)
Paula and Rodger Riney Family Foundation
ARTICLE ABSTRACT
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 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 multiple myeloma cell lines and primary cells. In addition, statins sensitize to apoptosis induced by MCL-1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in multiple myeloma, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize multiple myeloma cells to venetoclax by upregulating two proapoptotic 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 multiple myeloma.
BH3 mimetics including venetoclax hold promise for treatment of multiple myeloma but rational combinations are needed to broaden efficacy. This study presents mechanistic and clinical data to support addition of pitavastatin to venetoclax regimens in myeloma. The results open a new avenue for repurposing statins in blood cancer.
