<i>BLM</i> overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor-resistant <i>BRCA</i>-mutant ovarian cancer.

ABSTRACT: Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene (BRCA)-mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA-mutant HG

SUBMITTER: Gupta N 

PROVIDER: S-EPMC10758289 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature