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

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

doi:10.1016/j.ccell.2023.03.002

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

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 WuRugang Zhang

Experimental Therapeutics

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Pages (from-to)	740-756.e10
Journal	Cancer cell
Volume	41
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2023.03.002
State	Published - Apr 10 2023

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2023.03.002

Cite this

Zhou, W., Liu, H., Yuan, Z., Zundell, J., Towers, M., Lin, J., Lombardi, S., Nie, H., Murphy, B., Yang, T., Wang, C., Liao, L., Goldman, A. R., Kannan, T., Kossenkov, A. V., Drapkin, R., Montaner, L. J., Claiborne, D. T., Zhang, N., ... Zhang, R. (2023). Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis. Cancer cell, 41(4), 740-756.e10. https://doi.org/10.1016/j.ccell.2023.03.002

Zhou, W, Liu, H, Yuan, Z, Zundell, J, Towers, M, Lin, J, Lombardi, S, Nie, H, Murphy, B, Yang, T, Wang, C, Liao, L, Goldman, AR, Kannan, T, Kossenkov, AV, Drapkin, R, Montaner, LJ, Claiborne, DT, Zhang, N, Wu, S & Zhang, R 2023, 'Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis', Cancer cell, vol. 41, no. 4, pp. 740-756.e10. https://doi.org/10.1016/j.ccell.2023.03.002

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title = "Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis",

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 = "anti-PD-L1, ARID1A, humanized mouse model, immune checkpoint blockade, inflammasome, mevalonate pathway, ovarian cancer, Pyroptosis, statin, SWI/SNF",

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

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = apr,

day = "10",

doi = "10.1016/j.ccell.2023.03.002",

language = "English (US)",

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T1 - Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis

AU - Zhou, Wei

AU - Liu, Heng

AU - Yuan, Zhe

AU - Zundell, Joseph

AU - Towers, Martina

AU - Lin, Jianhuang

AU - Lombardi, Simona

AU - Nie, Hao

AU - Murphy, Brennah

AU - Yang, Tyler

AU - Wang, Chen

AU - Liao, Liping

AU - Goldman, Aaron R.

AU - Kannan, Toshitha

AU - Kossenkov, Andrew V.

AU - Drapkin, Ronny

AU - Montaner, Luis J.

AU - Claiborne, Daniel T.

AU - Zhang, Nan

AU - Wu, Shuai

AU - Zhang, Rugang

PY - 2023/4/10

Y1 - 2023/4/10

N2 - 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.

AB - 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.

KW - anti-PD-L1

KW - ARID1A

KW - humanized mouse model

KW - immune checkpoint blockade

KW - inflammasome

KW - mevalonate pathway

KW - ovarian cancer

KW - Pyroptosis

KW - statin

KW - SWI/SNF

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DO - 10.1016/j.ccell.2023.03.002

M3 - Article

C2 - 36963401

AN - SCOPUS:85151865542

SN - 1535-6108

VL - 41

SP - 740-756.e10

JO - Cancer cell

JF - Cancer cell

IS - 4

ER -

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

Abstract

Keywords

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