Targeting the Mevalonate Pathway Suppresses ARID1A-Inactivated Cancers by Promoting Pyroptosis

Authors

Wei Zhou
Heng Liu
Zhe Yuan
Joseph Zundell
Martina Towers
Jianhuang Lin
Simona Lombardi
Hao Nie
Brennah Murphy
Tyler Yang
Chen Wang
Liping Liao
Aaron R Goldman
Toshitha Kannan
Andrew V Kossenkov
Ronny Drapkin
Luis J Montaner
Daniel T Claiborne
Nan Zhang
Shuai Wu
Rugang Zhang

Publication Date

4-10-2023

Journal

Cancer Cell

Abstract

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.

Keywords

Humans, Female, Mice, Animals, Mevalonic Acid, Pyroptosis, Nuclear Proteins, Ovarian Neoplasms, Carcinoma, Mutation, DNA-Binding Proteins, Transcription Factors

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Associated Data

PMID: 36963401