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Sci Transl Med. 2018 Jun 13;10(445). pii: eaaq1240. doi: 10.1126/scitranslmed.aaq1240.

Statins enhance efficacy of venetoclax in blood cancers.

Author information

1
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.
2
Oncology Development, AbbVie Inc., North Chicago, IL 60064, USA. dfruman@uci.edu awroberts@comcast.net.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Oncology Development, AbbVie Inc., North Chicago, IL 60064, USA.
5
Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.
6
Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
7
Department of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
8
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA. dfruman@uci.edu awroberts@comcast.net.

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.

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