UC Irvine

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.