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

9 Scopus citations

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

ASJC Scopus subject areas

  • Medicine(all)

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    Lee, J. S., Roberts, A., Juarez, D., Vo, T. T. T., Bhatt, S., Herzog, L. O., Mallya, S., Bellin, R. J., Agarwal, S. K., Salem, A. H., Xu, T., Jia, J., Li, L., Hanna, J. R., Davids, M. S., Fleischman, A. G., O'Brien, S., Lam, L. T., Leverson, J. D., ... 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