Poly (ADP-ribose) polymerase inhibitor (PARPi,
olaparib) impairs the repair of
DNA single-strand breaks (SSBs), resulting in double-strand breaks (DSBs) that cannot be repaired efficiently in homologous recombination repair (HRR)-deficient
cancers such as BRCA1/2-mutant
cancers, leading to synthetic lethality. Despite the efficacy of
olaparib in the treatment of BRCA1/2 deficient
tumors, PARPi resistance is common. We hypothesized that the combination of
olaparib with
anticancer agents that disrupt HRR by targeting
ataxia telangiectasia and Rad3-related
protein (ATR) or
checkpoint kinase 1 (CHK1) may be an effective strategy to reverse
ovarian cancer resistance to
olaparib. Here, we evaluated the effect of
olaparib, the ATR inhibitor
AZD6738, and the CHK1 inhibitor
MK8776 alone and in combination on cell survival, colony formation, replication stress response (RSR)
protein expression, DNA damage, and apoptotic changes in BRCA2 mutated (PEO-1) and HRR-proficient BRCA wild-type (SKOV-3 and OV-90) cells. Combined treatment caused the accumulation of
DNA DSBs. PARP expression was associated with sensitivity to
olaparib or inhibitors of RSR. Synergistic effects were weaker when
olaparib was combined with CHK1i and occurred regardless of the BRCA2 status of
tumor cells. Because PARPi increases the reliance on ATR/CHK1 for
genome stability, the combination of PARPi with ATR inhibition suppressed
ovarian cancer cell growth independently of the efficacy of HRR. The present results were obtained at sub-lethal doses, suggesting the potential of these inhibitors as monotherapy as well as in combination with
olaparib.