Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors
Authors:
- Dennis JuarezDJDennis Juarez
- Roberta BuonoRBRoberta Buono
- Shannon M. MatulisSMShannon M. Matulis
- Vikas A. GuptaVGVikas A. Gupta
- Madeleine R. DuongMDMadeleine R. Duong
- Jacob YudionoJYJacob Yudiono
- Madhuri PaulMPMadhuri Paul
- Sharmila MallyaSMSharmila Mallya
- Grace DiepGDGrace Diep
- Peter HsinPHPeter Hsin
- Alexander LuALAlexander Lu
- Sang Mi SuhSSSang Mi Suh
Open Access
- 8 December 2023
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research Communications
- Vol. 3 (12) , 2497-2509
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.Keywords
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Funding Information
- HHS | National Institutes of Health (R21CA209341)
- HHS | National Institutes of Health (R35GM127071)
- HHS | National Institutes of Health (K08CA267055)
- HHS | National Institutes of Health (P30CA062203)
- HHS | National Institutes of Health (P30CA138292)
- HHS | National Institutes of Health (T32CA009054)
- American Cancer Society (IRG14-188-01)
- Leukemia and Lymphoma Society (TRP 6597-2)
- Paula and Rodger Riney Family Foundation
This publication has 81 references indexed in Scilit:
- Targeting p53 by small molecules in hematological malignanciesJournal of Hematology & Oncology, 2013
- ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing plateletsNature Medicine, 2013
- Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response pathway in multiple myeloma cellsLeukemia Research, 2011
- SUnSET, a nonradioactive method to monitor protein synthesisNature Methods, 2009
- Solid-phase extraction and liquid chromatography/tandem mass spectrometry assay for the determination of pitavastatin in human plasma and urine for application to Phase I clinical pharmacokinetic studiesJournal of Chromatography B, 2008
- Activation of the Integrated Stress Response Regulates Lovastatin-induced ApoptosisJournal of Biological Chemistry, 2007
- First clinical experience with simvastatin to overcome drug resistance in refractory multiple myelomaEuropean Journal of Haematology, 2007
- Determinants of sensitivity to lovastatin-induced apoptosis in multiple myelomaMolecular Cancer Therapeutics, 2007
- Structural insights into the degradation of Mcl-1 induced by BH3 domainsProceedings of the National Academy of Sciences, 2007
- The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinaseBlood, 2004