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,
Ryan J. Hansen,
Bryan Strouse,
Snezana Milutinovic,
Christian Hassig,
Matthew J. Wakefield,
Cassandra J. Vandenberg,
Clare L. Scott,
Fiona Simpkins
Affiliations
Haineng Xu
Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Sarah B. Gitto
Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Gwo-Yaw Ho
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
Sergey Medvedev
Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Kristy Shield-Artin
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
Hyoung Kim
Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Sally Beard
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Yasuto Kinose
Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Xiaolei Wang
Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Holly E. Barker
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
Gayanie Ratnayake
The Royal Women’s Hospital, Parkville, VIC 3052, Australia
Wei-Ting Hwang
Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA 19104, USA
Ryan J. Hansen
Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia
Bryan Strouse
Sierra Oncology, Inc, 885 West Georgia Street, Suite 2150, Vancouver, BC V6C 3E8, Canada
Snezana Milutinovic
Sierra Oncology, Inc, 885 West Georgia Street, Suite 2150, Vancouver, BC V6C 3E8, Canada
Christian Hassig
Sierra Oncology, Inc, 885 West Georgia Street, Suite 2150, Vancouver, BC V6C 3E8, Canada
Matthew J. Wakefield
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3010, Australia
Cassandra J. Vandenberg
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
Clare L. Scott
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; The Royal Women’s Hospital, Parkville, VIC 3052, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3010, Australia; Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia; Corresponding author
Fiona Simpkins
Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Summary: 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 (CCNE1amp) are associated with resistance to PARPi and platinum treatments. High replication stress in HRD and CCNE1amp 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 CCNE1amp HGSOC models. We demonstrated that SRA737 increased replication stress and induced subsequent cell death in vitro. SRA737 monotherapy in vivo prolonged survival in CCNE1amp models, suggesting a potential biomarker for CHK1i therapy. Combination SRA737 and PARPi therapy increased tumor regression in both PARPi-resistant and CCNE1amp patient-derived xenograft models, warranting further study in these HGSOC subgroups.
