Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis
ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppresses the growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1 antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation and in a humanized immunocompetent ARID1A mutant patient-derived OCCC mouse model. Our data indicate that inhibition of the mevalonate pathway simultaneously suppresses tumor cell growth and boosts antitumor immunity by promoting pyroptosis, which synergizes with ICB in suppressing ARID1A-mutated cancers.
Journal
Cancer CellAuthors
Funding
Cancer Center Support GrantLipids and Myeloid Cell Function in CancerAnimal Shared ResourceProject 3: Investigating new treatment approaches based on DNA repair vulnerability in ARID1A mutated type I ovarian cancerIntegrative Approach to Comprehensive Analysis of High Throughput Data on a Cancer Center LevelMechanistic basis and therapeutic strategies for ARID1A mutation in ovarian cancerSynthetic lethality based combination approaches to ARID1A mutation in ovarian cancerMetabolic basis of ARID1A-mutated ovarian cancerTraining Program in Basic Cancer ResearchTargeting EZH2 in CARM1-expressing epithelial ovarian cancerUS Department of Defense FundingCongressionally Directed Medical Research Programs Grant OC180109Congressionally Directed Medical Research Programs Grant OC180192Congressionally Directed Medical Research Programs Grant OC190181Congressionally Directed Medical Research Programs Grant OC210124Cancer Prevention and Research Institute of Texas FundingUniversity of Texas MD Anderson Cancer Center FundingThe Philadelphia Foundation FundingOvarian Cancer Research Fund Alliance FundingAnimal Shared ResourceCancer Center Support GrantProject 3: Investigating new treatment approaches based on DNA repair vulnerability in ARID1A mutated type I ovarian cancerTargeting EZH2 in CARM1-expressing epithelial ovarian cancerNational Institutes of Health Grant R01CA1665065Mechanistic basis and therapeutic strategies for ARID1A mutation in ovarian cancerSynthetic lethality based combination approaches to ARID1A mutation in ovarian cancerMetabolic basis of ARID1A-mutated ovarian cancerWistar Institute Funding