BRCA2 reversion mutation-independent resistance to PARP inhibition through impaired DNA prereplication complex function.

ABSTRACT: Recent approvals of polymeric adenosine diphosphate ribose (poly(ADP-ribose) polymerase inhibitors (PARPi) for BRCA-mutant metastatic castration resistant prostate cancer necessitate an understanding of the factors that shape sensitivity and resistance. Reversion mutations that restore homologous recombination (HR) repair are detected in ~50 to 80% of BRCA-mutant patients who respond but subsequently relapse, but there is currently little insight into why only ~50% of BRCA-mutant patients display upfront resistance. To address this question, we performed a genome-wide CRISPR screen to identify genomic determinants of PARPi resistance in murine Brca2^Δ/Δ prostate organoids genetically engineered in a manner that precludes the development of reversion mutations. Remarkably,

SUBMITTER: Pappas K 

PROVIDER: S-EPMC12167974 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature