There is a resurgence of interest in understanding the role of the mevalonate pathway in cancer. The on-target anti-cancer effects of the clinical mevalonate inhibitors, statins, are plentiful and diverse across several cancer models. As pan-cancer approaches have not identified a unifying theory for the observed mevalonate pathway dependence in cancers, we focus on blood cancers which have collectively demonstrated the greatest sensitivity to mevalonate pathway inhibition. In blood cancers, it is widely published that statins induce the non-inflammatory cell death modality, apoptosis. The success of apoptosis induction in blood cancers using inhibitors of BCL2 Homology 3 (BH3) domains of pro-survival BCL2 family members known as BH3 mimetics provides an impetus and means to understand the apoptotic mechanisms of mevalonate dependence. Herein, we describe mechanisms by which mevalonate pathway inhibitors sensitize to BH3 mimetics in blood cancers and our efforts to understand the mevalonate pathway outputs that promote blood cancer survival.

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.

Significance