Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in BRCA-Mutant Ovarian Cancer Models.

ABSTRACT: Purpose: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA-mutant (BRCA^MUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression.Experimental Design: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776), or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell cycle, genome instability, and apoptosis were evaluated in BRCA1/2^MUT HGSOC cells. Tumor growth in vivo was evaluated using a BRCA2^MUT patient-derived xenograft (PDX) model.Results: PARPi monotherapy resulted in a decrease in BRC

SUBMITTER: Kim H 

PROVIDER: S-EPMC5474193 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature