American Association for Cancer Research
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FIGURE 3 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

Simvastatin induces p53-independent PUMA upregulation. A, A BCL2 family model figure depicting protein interactions and how BH3 mimetics can cooperate with apoptotic sensitizers. B, A representative Western blot analysis of statin-insensitive (red) and statin-sensitive (black) MMCLs treated for 16 hours with 10 µmol/L simvastatin. n = 3. C, Quantification by densitometry of PUMA upregulation. Mean ± SD, n = 3, significance (α<0.05) determined by one-sample t test of log-transformed fold changes against the value of 0. *, P < 0.05; **, P < 0.01. D, Representative (n = 3) Western blots showing that PUMA upregulation by 10 µmol/L simvastatin is not dependent on the transcriptional activity of p53. Expression of the p53 dominant negative, GSE56, was accomplished in three MMCLs, L363, NCI-H929, and OPM2 wherein the basal p53 status is mutated [*L363 cells have a point mutation in exon7/intron 7 splicing junction (base C782G) that impairs splicing of intron 7], wild-type, and mutated (R175H), respectively. GSE56 expression was confirmed with a rodent-specific p53 antibody (Cell Signaling Technology# 32532). Activation of p53 using 10 µmol/L of the topoisomerase inhibitor, etoposide, was used as a positive control to confirm blockade of p53 activation of PUMA upregulation.


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Leukemia and Lymphoma Society (LLS)

Paula and Rodger Riney Family Foundation



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.