Statins enhance efficacy of venetoclax in blood cancers

J. Scott Lee, Andrew Roberts, Dennis Juarez, Thanh Trang T. Vo, Shruti Bhatt, Lee Or Herzog, Sharmila Mallya, Richard J. Bellin, Suresh K. Agarwal, Ahmed Hamed Salem, Tu Xu, Jia Jia, Lingxiao Li, John R. Hanna, Matthew S. Davids, Angela G. Fleischman, Susan O'Brien, Lloyd T. Lam, Joel D. Leverson, Anthony LetaiJonathan H Schatz, David A. Fruman

Research output: Contribution to journalArticle

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Abstract

Statins have shown promise as anticancer agents in experimental and epidemiologic research. However, any benefit that they provide is likely context-dependent, for example, applicable only to certain cancers or in combination with specific anticancer drugs. We report that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) using statins enhances the proapoptotic activity of the B cell lymphoma-2 (BCL2) inhibitor venetoclax (ABT-199) in primary leukemia and lymphoma cells but not in normal human peripheral blood mononuclear cells. By blocking mevalonate production, HMGCR inhibition suppressed protein geranylgeranylation, resulting in up-regulation of proapoptotic protein p53 up-regulated modulator of apoptosis (PUMA). In support of these findings, dynamic BH3 profiling confirmed that statins primed cells for apoptosis. Furthermore, in retrospective analyses of three clinical studies of chronic lymphocytic leukemia, background statin use was associated with enhanced response to venetoclax, as demonstrated by more frequent complete responses. Together, this work provides mechanistic justification and clinical evidence to warrant prospective clinical investigation of this combination in hematologic malignancies.

Original languageEnglish (US)
Article numbereaaq1240
JournalScience Translational Medicine
Volume10
Issue number445
DOIs
StatePublished - Jun 13 2018
Externally publishedYes

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Neoplasms
Oxidoreductases
Protein Prenylation
Apoptosis
Mevalonic Acid
B-Cell Lymphoma
Hematologic Neoplasms
B-Cell Chronic Lymphocytic Leukemia
Antineoplastic Agents
Lymphoma
Blood Cells
Leukemia
Up-Regulation
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide
Research
Pharmaceutical Preparations
Proteins
3-hydroxy-3-methylglutaryl-coenzyme A

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lee, J. S., Roberts, A., Juarez, D., Vo, T. T. T., Bhatt, S., Herzog, L. O., ... Fruman, D. A. (2018). Statins enhance efficacy of venetoclax in blood cancers. Science Translational Medicine, 10(445), [eaaq1240]. https://doi.org/10.1126/scitranslmed.aaq1240

Statins enhance efficacy of venetoclax in blood cancers. / Lee, J. Scott; Roberts, Andrew; Juarez, Dennis; Vo, Thanh Trang T.; Bhatt, Shruti; Herzog, Lee Or; Mallya, Sharmila; Bellin, Richard J.; Agarwal, Suresh K.; Salem, Ahmed Hamed; Xu, Tu; Jia, Jia; Li, Lingxiao; Hanna, John R.; Davids, Matthew S.; Fleischman, Angela G.; O'Brien, Susan; Lam, Lloyd T.; Leverson, Joel D.; Letai, Anthony; Schatz, Jonathan H; Fruman, David A.

In: Science Translational Medicine, Vol. 10, No. 445, eaaq1240, 13.06.2018.

Research output: Contribution to journalArticle

Lee, JS, Roberts, A, Juarez, D, Vo, TTT, Bhatt, S, Herzog, LO, Mallya, S, Bellin, RJ, Agarwal, SK, Salem, AH, Xu, T, Jia, J, Li, L, Hanna, JR, Davids, MS, Fleischman, AG, O'Brien, S, Lam, LT, Leverson, JD, Letai, A, Schatz, JH & Fruman, DA 2018, 'Statins enhance efficacy of venetoclax in blood cancers', Science Translational Medicine, vol. 10, no. 445, eaaq1240. https://doi.org/10.1126/scitranslmed.aaq1240
Lee JS, Roberts A, Juarez D, Vo TTT, Bhatt S, Herzog LO et al. Statins enhance efficacy of venetoclax in blood cancers. Science Translational Medicine. 2018 Jun 13;10(445). eaaq1240. https://doi.org/10.1126/scitranslmed.aaq1240
Lee, J. Scott ; Roberts, Andrew ; Juarez, Dennis ; Vo, Thanh Trang T. ; Bhatt, Shruti ; Herzog, Lee Or ; Mallya, Sharmila ; Bellin, Richard J. ; Agarwal, Suresh K. ; Salem, Ahmed Hamed ; Xu, Tu ; Jia, Jia ; Li, Lingxiao ; Hanna, John R. ; Davids, Matthew S. ; Fleischman, Angela G. ; O'Brien, Susan ; Lam, Lloyd T. ; Leverson, Joel D. ; Letai, Anthony ; Schatz, Jonathan H ; Fruman, David A. / Statins enhance efficacy of venetoclax in blood cancers. In: Science Translational Medicine. 2018 ; Vol. 10, No. 445.
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