figure
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 Pitavastatin is three times more potent than simvastatin in cell-based assays of apoptosis and biomarker responses, and increases apoptosis in combination with venetoclax in a subset of patient samples treated ex vivo. A, Cell Titer Glo was used to assess viability in statin/BH3 mimetic combinations after 48 hours; % viable cells was normalized to vehicle. Mean ± SD, n = 3. B, Pitavastatin increases PUMA and blocks prenylation of RAP1A at concentrations lower than simvastatin. C, Results of a glucocorticoid resistance cell line models MM.1S (sensitive) and MM.1R (resistant) after 48 hours treatment. Mean ± SD; n = 3; *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001, one-way ANOVA with Tukey post-test correction for multiple comparisons. D, Buffy coats from multiple myeloma patient bone marrow aspirates were treated in vitro with 1 µmol/L pitavastatin and 10 nmol/L venetoclax for 24 hours before staining with CD45, CD38, and Annexin V to assess viability.
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.
