CHK1 inhibitor SRA737 is active in PARP inhibitor resistant and CCNE1 amplified ovarian cancer

Xu, H; Gitto, SB; Ho, GY; Medvedev, S; Shield-Artin, K; Kim, H; Beard, S; Kinose, Y; Wang, X; Barker, HE; Ratnayake, G; Hwang, WT; Australian Ovarian Cancer Study; Hansen, RJ; Strouse, B; Milutinovic, S; Hassig, C; Wakefield, MJ; Vandenberg, CJ; Scott, CL; Simpkins, F

Author(s): Xu, H; Gitto, SB; Ho, GY; Medvedev, S; Shield-Artin, K; Kim, H; Beard, S; Kinose, Y; Wang, X; Barker, HE; Ratnayake, G; Hwang, WT; Australian Ovarian Cancer Study; 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
Publication Type: Research article
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
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1016/j.isci.2024.109978
Open Access at Publisher's Site: https://doi.org/10.1016/j.isci.2024.109978
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-09-03 07:47:01

Last Modified: 2024-09-03 07:49:20