TY - JOUR
T1 - CHK1 inhibitor SRA737 is active in PARP inhibitor resistant and CCNE1 amplified ovarian cancer
AU - Xu, Haineng
AU - Gitto, Sarah B.
AU - Ho, Gwo-Yaw
AU - Medvedev, Sergey
AU - Shield-Artin, Kristy
AU - Kim, Hyoung
AU - Beard, Sally
AU - Kinose, Yasuto
AU - Wang, Xiaolei
AU - Barker, Holly E.
AU - Ratnayake, Gayanie
AU - Hwang, Wei Ting
AU - Hansen, Ryan J.
AU - Strouse, Bryan
AU - Milutinovic, Snezana
AU - Hassig, Christian
AU - Wakefield, Matthew J.
AU - Vandenberg, Cassandra J.
AU - Scott, Clare L.
AU - Simpkins, Fiona
AU - Australian Ovarian Cancer Study Group (AOCS)
N1 - Funding Information:
This work was made possible through funding from NIH ( R37-CA-215436 , P50-CA-228991 , R01-CA-278882 ), the UPenn Basser Center Team Grant , Penn Ovarian Cancer Translational Center of Excellence , and the Ovarian Cancer Research Center BioTrust awarded to F.S.; The Foundation for Women's Cancer (FWC) St. Louis Ovarian Cancer Awareness and Caring Together Research Grant, UPenn/John Hopkins SPORE pilot grant awarded to H.X.; National Health and Medical Council Australia ( 1062702 ), The Stafford Fox Medical Research Foundation , the Cancer Council Victoria Sir Edward Dunlop Fellowship in Cancer Research , and the Victorian Cancer Agency (Clinical Fellowships CRF10\u201320 , CRF16014 ) awarded to C.L.S. G.H. was supported by a Research Training Program Scholarship provided by the Australian Centre for Geomechanics and the University of Melbourne ; with additional support from CRC for Cancer Therapeutics. The Australian Ovarian Cancer Study Group was supported by the US Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania and The Cancer Foundation of Western Australia (Multi-State Applications 191, 211 and 182) and the National Health and Medical Research Council of Australia (NHMRC; ID199600; ID400413 and ID400281).
Funding Information:
The authors thank the Penn Ovarian Cancer Translational Center of Excellence, Ovarian Cancer Research Center, Penn Stem Cell and Xenograft Core for technical support with animal studies and equipment, and University of Pennsylvania Histology cores and Mei Zheng for immunohistochemistry staining. The authors thank Silvia Stoev, Kathy Barber, and Rachel Hancock for technical assistance with the animal studies and the WEHI Bioservices Facility for their support; WEHI Histology and the Center for Dynamic Imaging for IHC staining and analysis. We thank Clovis Oncology for funding FoundationOne assay analysis. The AOCS also acknowledges the cooperation of the participating institutions in Australia and acknowledges the contribution of the study nurses, research assistants and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www.aocstudy.org . We would like to thank all the women who participated in these research programs.
Publisher Copyright:
© 2024
PY - 2024/7/19
Y1 - 2024/7/19
N2 - 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.
AB - 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.
KW - Cancer
KW - Cell biology
KW - Molecular biology
UR - http://www.scopus.com/inward/record.url?scp=85196399378&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2024.109978
DO - 10.1016/j.isci.2024.109978
M3 - Article
C2 - 39021796
AN - SCOPUS:85196399378
SN - 2589-0042
VL - 27
SP - 1
EP - 22
JO - iScience
JF - iScience
IS - 7
M1 - 109978
ER -
