CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer

Takuya Tsujino, Tomoaki Takai, Kunihiko Hinohara, Fu Gui, Takeshi Tsutsumi, Xiao Bai, Chenkui Miao, Chao Feng, Bin Gui, Zsofia Sztupinszki, Antoine Simoneau, Ning Xie, Ladan Fazli, Xuesen Dong, Haruhito Azuma, Atish D. Choudhury, Kent W. Mouw, Zoltan Szallasi, Lee Zou, Adam S. Kibel and Li Jia ()
Additional contact information
Takuya Tsujino: Brigham and Women’s Hospital & Harvard Medical School
Tomoaki Takai: Brigham and Women’s Hospital & Harvard Medical School
Kunihiko Hinohara: Dana-Farber Cancer Institute & Harvard Medical School
Fu Gui: Brigham and Women’s Hospital & Harvard Medical School
Takeshi Tsutsumi: Brigham and Women’s Hospital & Harvard Medical School
Xiao Bai: Brigham and Women’s Hospital & Harvard Medical School
Chenkui Miao: Brigham and Women’s Hospital & Harvard Medical School
Chao Feng: Brigham and Women’s Hospital & Harvard Medical School
Bin Gui: Brigham and Women’s Hospital & Harvard Medical School
Zsofia Sztupinszki: Boston Children’s Hospital
Antoine Simoneau: Massachusetts General Hospital & Harvard Medical School
Ning Xie: Vancouver General Hospital
Ladan Fazli: Vancouver General Hospital
Xuesen Dong: Vancouver General Hospital
Haruhito Azuma: Osaka Medical and Pharmaceutical University
Atish D. Choudhury: Dana-Farber Cancer Institute & Harvard Medical School
Kent W. Mouw: Dana-Farber Cancer Institute & Brigham and Women’s Hospital & Harvard Medical School
Zoltan Szallasi: Boston Children’s Hospital
Lee Zou: Massachusetts General Hospital & Harvard Medical School
Adam S. Kibel: Brigham and Women’s Hospital & Harvard Medical School
Li Jia: Brigham and Women’s Hospital & Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed (up to 14%) in prostate cancer, renders cells hypersensitive to PARP inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer.

Date: 2023
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DOI: 10.1038/s41467-023-35880-y

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