CHK1 inhibitor SRA737 is active in PARP inhibitor resistant and CCNE1 amplified ovarian cancer
- Author(s)
- Xu, H; Australian Ovarian Cancer, Study; Gitto, SB; Ho, GY; Medvedev, S; Shield-Artin, K; Kim, H; Beard, S; Kinose, Y; Wang, X; Barker, HE; Ratnayake, G; Hwang, WT; Hansen, RJ; Strouse, B; Milutinovic, S; Hassig, C; Wakefield, MJ; Vandenberg, CJ; Scott, CL; Simpkins, F;
- Details
- Publication Year 2024-07-19,Volume 27,Issue #7,Page 109978
- Journal Title
- iScience
- Abstract
- 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.
- Publisher
- Cell Press
- Keywords
- Cancer; Cell biology; Molecular biology
- Research Division(s)
- Bioinformatics; Bioinformatics; Cancer Biology And Stem Cells
- PubMed ID
- 39021796
- Publisher's Version
- https://doi.org/10.1016/j.isci.2024.109978
- Open Access at Publisher's Site
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Creation Date: 2024-06-28 10:39:13
Last Modified: 2024-07-26 09:25:46