Chemoresistance ofTP53mutant AML requires the mevalonate byproduct, GGPP, for regulation of ROS and induction of a mitochondria stress response

Abstract

AbstractAcute myeloid leukemia (AML) with mutations in the tumor suppressor gene,TP53(TP53mutAML), is fatal with a median survival of only 6 months. RNA sequencing on purified AML patient samples showTP53mutAML has higher expression of mevalonate pathway genes. We retrospectively identified a survival benefit inTP53mutAML patients who received chemotherapy concurrently with a statin, which inhibits the mevalonate pathway. Mechanistically,TP53mutAML resistance to standard AML chemotherapy, cytarabine (AraC), correlates with increased mevalonate pathway activity and a mitochondria stress response with increased mitochondria mass and oxidative phosphorylation. Pretreatment with a statin reverses these effects and chemosensitizesTP53mutAML cell lines and primary samplesin vitroandin vivo. Mitochondria-dependent chemoresistance requires the geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway and novel GGPP-dependent synthesis of glutathione to manage AraC-induced reactive oxygen species (ROS). Overall, we show that the mevalonate pathway is a novel therapeutic target inTP53mutAML.SignificanceChemotherapy-persistingTP53mutAML cells induce a mitochondria stress response that requires mevalonate byproduct, GGPP, through its novel role in glutathione synthesis and regulation of mitochondria metabolism. We provide insight into prior failures of the statin family of mevalonate pathway inhibitors in AML. We identify clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need ofTP53mutAML.