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CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer
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CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer
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Journal Article
CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer
2023
Overview
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.
Identifying prostate cancer patients who may respond well to PARP inhibitors is important for their success in the clinic. Here, using a genome-wide CRISPR-Cas9 knockout screen, the authors identify
MMS22L
as a biomarker for sensitivity to PARP inhibition in BRCA1/2-proficient prostate cancer.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/2
/ 13/31
/ 45
/ 45/23
/ 49
/ 49/105
/ 49/15
/ 49/91
/ Antineoplastic Agents - pharmacology
/ CRISPR
/ Genes
/ Genomes
/ Homologous recombination repair
/ Humanities and Social Sciences
/ Humans
/ Male
/ Mutation
/ Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
/ Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use
/ Prostatic Neoplasms - drug therapy
/ Prostatic Neoplasms - genetics
/ Science
/ Tumors
