Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis

Cancer Cell. 2023 Apr 10;41(4):740-756.e10. doi: 10.1016/j.ccell.2023.03.002. Epub 2023 Mar 23.


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: ARID1A; Pyroptosis; SWI/SNF; anti-PD-L1; humanized mouse model; immune checkpoint blockade; inflammasome; mevalonate pathway; ovarian cancer; statin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinoma*
  • DNA-Binding Proteins / genetics
  • Female
  • Humans
  • Mevalonic Acid
  • Mice
  • Mutation
  • Nuclear Proteins / genetics
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / metabolism
  • Pyroptosis
  • Transcription Factors / genetics


  • Mevalonic Acid
  • Nuclear Proteins
  • ARID1A protein, human
  • DNA-Binding Proteins
  • Transcription Factors
  • Arid1a protein, mouse