CHK1 Inhibitor SRA737 is Active in PARP Inhibitor Resistant and Amplified Ovarian Cancer

High-grade serous ovarian cancers (HGSOCs) with homologous recombination deficiency (HRD) are initially responsive to poly (ADP-ribose) polymerase inhibitors (PARPi), but resistance ultimately emerges. HGSOC with amplification ( ) are associated with resistance to PARPi and platinum treatments. High replication stress in HRD and HGSOC leads to increased reliance on checkpoint kinase 1 (CHK1), a key regulator of cell cycle progression and the replication stress response. Here, we investigated the anti-tumor activity of the potent, highly selective, orally bioavailable CHK1 inhibitor (CHK1i), SRA737, in both acquired PARPi-resistant mutant and HGSOC models. We demonstrated that SRA737 increased replication stress and induced subsequent cell death . SRA737 monotherapy prolonged survival in models, suggesting a potential biomarker for CHK1i therapy. Combination SRA737 and PARPi therapy increased tumor regression in both PARPi-resistant and patient-derived xenograft models, warranting further study in these HGSOC subgroups.