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

• Type of Material: Article
• Authors: Dennis Juarez, University of California, Irvine; Roberta Buono, University of California, Irvine; Shannon M Matulis, Emory University; Vikas Gupta, Emory University; Madeleine Duong, University of California, Irvine; Jacob Yudiono, University of California, Irvine; Madhuri Paul, University of California, Irvine; Sharmila Mallya, University of California, Irvine; Grace Diep, University of California, Irvine; Peter Hsin, University of California, Irvine; Alexander Lu, University of California, Irvine; Sang Mi Suh, University of California, Irvine; Vy M. Dong, University of California, Irvine; Andrew W. Roberts, AbbVie Inc.; Joel D. Leverson, AbbVie Inc.; Muhammad Jalaluddin, AbbVie Inc.; Zhuangzhuang Liu, AbbVie Inc.; Orlando F. BUeno, AbbVie Inc.; Lawrence Boise, Emory University; David A. Fruman, University of California, Irvine
• Language: English
• Date: 2023-12-08
• Publisher: American Association for Cancer Research
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors; Published by the American Association for Cancer Research
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1158/2767-9764.CRC-23-0350
• Title of Journal or Parent Work: Cancer Research Communications
• Volume: 3
• Issue: 12
• Start Page: 2497
• End Page: 2509
• Grant/Funding Information: This work was supported by a grant from the Leukemia and Lymphoma Society Translational Research Program (D.A. Fruman, PI; L.H. Boise, co-investigator), and by NIH grants R21CA209341 (to D.A. Fruman), R35GM127071 (to V.M. Dong), K08CA267055 (to V.A. Gupta), and Cancer Center Support Grants P30CA062203 (UCI Chao Family Comprehensive Cancer Center) P30CA138292 (Emory University). D. Juarez was supported by NIH T32 grant CA009054, L.H. Boise by the Paula and Rodger Riney Family Foundation, and V.A. Gupta by an Institutional Research Grant from the American Cancer Society (IRG14-188-01).
• Keywords: MCL-1; BCL2 inhibitor venetoclax; BH3 Mimetics; myeloma cells
• Research Categories: Biology, Cell; Health Sciences, Oncology

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. Significance: 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.