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

Haineng Xu; Sarah B Gitto; Gwo-Yaw Ho; Sergey Medvedev; Kristy Shield-Artin; Hyoung Kim; Sally Beard; Yasuto Kinose; Xiaolei Wang; Holly E Barker; Gayanie Ratnayake; Wei-Ting Hwang; Australian Ovarian Cancer Study; Ryan J Hansen; Bryan Strouse; Snezana Milutinovic; Christian Hassig; Matthew J Wakefield; Cassandra J Vandenberg; Clare L Scott; Fiona Simpkins

doi:10.1016/j.isci.2024.109978

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

iScience. 2024 May 15;27(7):109978. doi: 10.1016/j.isci.2024.109978. eCollection 2024 Jul 19.

Authors

Haineng Xu¹, Sarah B Gitto^{1

2}, Gwo-Yaw Ho^{3

4}, Sergey Medvedev¹, Kristy Shield-Artin^{3

4}, Hyoung Kim¹, Sally Beard³, Yasuto Kinose¹, Xiaolei Wang¹, Holly E Barker^{3

4}, Gayanie Ratnayake⁵, Wei-Ting Hwang⁶; Australian Ovarian Cancer Study; Ryan J Hansen⁷, Bryan Strouse⁸, Snezana Milutinovic⁸, Christian Hassig⁸, Matthew J Wakefield^{3

9}, Cassandra J Vandenberg^{3

4}, Clare L Scott^{3

4

5

9

10}, Fiona Simpkins¹

Affiliations

¹ Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁴ Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
⁵ The Royal Women's Hospital, Parkville, VIC 3052, Australia.
⁶ Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia.
⁸ Sierra Oncology, Inc, 885 West Georgia Street, Suite 2150, Vancouver, BC V6C 3E8, Canada.
⁹ Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3010, Australia.
¹⁰ Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia.

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.

Keywords: Cancer; Cell biology; Molecular biology.