LAUSR

Statins cooperate with proapoptotic drugs to enhance tumor killing in blood cancers. Yet another health benefit of statins Statins, common drugs used for the treatment of high cholesterol, may have found another potential application. In addition to their effects on the cholesterol pathway, statins can also inhibit the activity of BCL2 and related proteins, which interfere with apoptosis in many cancer types. In light of this connection, Lee et al. examined the effects of statins on several types of leukemias and lymphomas. The authors determined that statins prime cancer cells for apoptosis and work in synergy with drugs such as venetoclax, an inhibitor of BCL2. In addition to demonstrating this synergy in mouse models, the authors provided data from three studies of patients with chronic lymphocytic leukemia, showing that patients receiving statins had better clinical responses to venetoclax. 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.