Statins enhance efficacy of venetoclax in blood cancers.

Published

Journal Article

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.

Full Text

Cited Authors

  • Lee, JS; Roberts, A; Juarez, D; Vo, T-TT; Bhatt, S; Herzog, L-O; 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

Published Date

  • June 2018

Published In

Volume / Issue

  • 10 / 445

PubMed ID

  • 29899021

Pubmed Central ID

  • 29899021

Electronic International Standard Serial Number (EISSN)

  • 1946-6242

International Standard Serial Number (ISSN)

  • 1946-6234

Digital Object Identifier (DOI)

  • 10.1126/scitranslmed.aaq1240

Language

  • eng