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FIGURE 1 from Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors

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posted on 2023-12-08, 14:20 authored by Dennis Juarez, Roberta Buono, Shannon M. Matulis, Vikas A. Gupta, Madeleine Duong, Jacob Yudiono, Madhuri Paul, Sharmila Mallya, Grace Diep, Peter Hsin, Alexander Lu, Sang Mi Suh, Vy M. Dong, Andrew W. Roberts, Joel D. Leverson, Muhammad Jalaluddin, Zhuangzhuang Liu, Orlando F. Bueno, Lawrence H. Boise, David A. Fruman

Statins significantly improve responses in a retrospective analysis of venetoclax clinical trials in R/R multiple myeloma. Results of patients with R/R multiple myeloma from venetoclax clinical trials receiving the standard therapy of Dex and a proteasome inhibitor (bortezomib for the phase Ib trial (NCT01794507 also known as M12-901) and carfilzomib for the ongoing phase II trial (NCT02899052 also known as M15-538) were pooled for post hoc analysis of background statin use on responses to therapy. A, Univariate analysis of the pooled trials assessing background statin use on response to therapy identified a significant difference in the proportion of subjects achieving sCR that is appreciated in each individual study (***, P < 0.001). B, No patient on statins experienced progressive disease (PD) in either individual study, resulting in a significant difference in the pooled analysis (*, P < 0.05). C, Multivariate analysis to evaluate known independent variables that affect patient outcomes, including prior lines of therapy, cytogenetic risk, and t(11;14) status in relation to statin use on patient responses. Statin use trended closer to support association with CR or better when accounting for prior lines of therapy, while t(11;14) and cytogenetic risk had no association with CR or better. No high-risk patients achieved sCR, thus cytogenetic risk was dropped from multivariate analysis of sCR. Neither prior lines of therapy nor t(11;14) status were associated with sCR, while statin use was strongly associated with increased rates of sCR (**, P < 0.01).

Funding

HHS | National Institutes of Health (NIH)

American Cancer Society (ACS)

Leukemia and Lymphoma Society (LLS)

Paula and Rodger Riney Family Foundation

History

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.