2024/05/15 by Haineng Xu, Sarah B. Gitto, Gwo‐Yaw Ho +17 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #BRCA gene mutations in cancer #DNA Repair Mechanisms #PARP inhibition in cancer therapy
paper · pdf · doi:10.1016/j.isci.2024.109978
openalex publication_date 2024/05/15 · openalex created_date 2024/05/16 · openalex updated_date 2026/08/04
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 CCNE1 amplification ( CCNE1 amp ) are associated with resistance to PARPi and platinum treatments. High replication stress in HRD and CCNE1 amp 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 BRCA1/2 mutant and CCNE1 amp HGSOC models. We demonstrated that SRA737 increased replication stress and induced subsequent cell death in vitro . SRA737 monotherapy in vivo prolonged survival in CCNE1 amp models, suggesting a potential biomarker for CHK1i therapy. Combination SRA737 and PARPi therapy increased tumor regression in both PARPi-resistant and CCNE1 amp patient-derived xenograft models, warranting further study in these HGSOC subgroups.