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 (MM) 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 MM cell lines and primary cells. Additionally, statins sensitize to apoptosis induced by MCL1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in MM, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize MM cells to venetoclax by upregulating two pro-apoptotic 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 MM

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2023
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Supplementary data

Figure S1

Figure S1 contains additional data from retrospective analysis of venetoclax clinical trials in MM

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Figure S2

Supplementary Figure 2 contains PFS data from venetoclax clinical trials in MM

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Figure S3

Supplementary Figure 3 contains additional viability assay data and synergy contour plots

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Figure S4

Supplementary Figure 4 contains BH3 profiling data, and viability assays in cells expressing p53 dominant negative

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Figure S5

Supplementary Figure 5 contains viability data and PUMA expression data from PBMCs

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Figure S6

Supplementary Figure 6 contains viability data from cells treated with the GGPP synthase inhibitor TH-Z145

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Figure S7

Supplementary Figure 7 contains data comparing pitavastatin with simavastatin in western blots (panel A) and BH3 profiling data with pitavastatin (panel B).

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Figure S8

Supplementary Figure 8 contains data on GILZ mRNA expression in MM1S and MM1R cells

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Figure S9

Supplementary Figure 9 contains data on L363 cells with PUMA (BBC3) knockout or inducible knockdown.

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Figure S10

Supplementary Figure 10 contains additional data on ISR-dependent changes in protein synthesis rates and viability.

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Figure S11

Supplementary Figure 11 presents data showing that pitavastatin does not activate ISR in AML cell lines.

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Figure S12

Supplementary Figure 12 contains additional data on the role of PERK in statin-induced ISR in MM cell lines.

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Figure S13

Supplementary Figure 13 presents data on Cas9-mediated NOXA and PUMA deletion in KMS18 cells (panel A) and viability assays in cells with PUMA knockdown and ISRIB treatment (panel B).

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Table S1

Supplementary Table S1 presents statistical analysis of pooled clinical trial data on R/R MM patient response to venetoclax treatment, comparing statin users to non-statin users.

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Table S2

Supplementary Table S2 presents statistical analysis of pooled clinical trial data on R/R MM patient response to venetoclax treatment, comparing one prior line of therapy to >1 prior line.

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Table S3

Supplementary Table S3 presents statistical analysis of pooled clinical trial data on R/R MM patient response to venetoclax treatment, comparing t11;14 patients to non-t11;14.

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Table S4

Supplementary Table S4 presents statistical analysis of pooled clinical trial data on R/R MM patient response to venetoclax treatment, comparing standard risk to high risk patients.

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Table S5

Supplementary Table S5 presents multivariate analysis of pooled clinical trial data on R/R MM patients achieving complete response (CR) or better -- variables include statin use, t11;14 status, prior lines of therapy, cytogenetic risk.

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Table S6

Supplementary Table S6 presents multivariate analysis of pooled clinical trial data on R/R MM patients achieving stringent complete response (sCR) -- variables include statin use, t11;14 status, prior lines of therapy, cytogenetic risk.

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Table S7

Supplementary Table S7 includes IC50 data for BH3 mimetic drugs in AML cell lines, without or with simvastatin.

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Table S8

Supplementary Table S8 provides synergy scores using BLISS and HSA algorithms.

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Table S9

Supplementary Table S9 shows the cytogenetic characteristics of the MM patients whose bone marrow cells were studied in Figure 4D.

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