Xu Haineng, Gitto Sarah B, Ho Gwo-Yaw, Medvedev Sergey, Shield-Artin Kristy, Kim Hyoung, Beard Sally, Kinose Yasuto, Wang Xiaolei, Barker Holly E, Ratnayake Gayanie, Hwang Wei-Ting, Hansen Ryan J, Strouse Bryan, Milutinovic Snezana, Hassig Christian, Wakefield Matthew J, Vandenberg Cassandra J, Scott Clare L, Simpkins Fiona
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.
iScience. 2024 May 15;27(7):109978. doi: 10.1016/j.isci.2024.109978. eCollection 2024 Jul 19.
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 amplification ( ) are associated with resistance to PARPi and platinum treatments. High replication stress in HRD and 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 mutant and HGSOC models. We demonstrated that SRA737 increased replication stress and induced subsequent cell death . SRA737 monotherapy prolonged survival in models, suggesting a potential biomarker for CHK1i therapy. Combination SRA737 and PARPi therapy increased tumor regression in both PARPi-resistant and patient-derived xenograft models, warranting further study in these HGSOC subgroups.
具有同源重组缺陷（HRD）的高级别浆液性卵巢癌（HGSOC）最初对聚（ADP-核糖）聚合酶抑制剂（PARPi）有反应，但最终会产生耐药性。伴有 扩增（ ）的HGSOC与对PARPi和铂类治疗的耐药性相关。HRD和 HGSOC中的高复制应激导致对细胞周期进程和复制应激反应的关键调节因子——检查点激酶1（CHK1）的依赖性增加。在此，我们研究了强效、高度选择性、口服生物利用度高的CHK1抑制剂（CHK1i）SRA737在获得性PARPi耐药 突变体和 HGSOC模型中的抗肿瘤活性。我们证明SRA737增加了复制应激并诱导随后的细胞死亡。SRA737单药治疗延长了 模型中的生存期，提示CHK1i治疗的潜在生物标志物。SRA737与PARPi联合治疗在PARPi耐药和 患者来源的异种移植模型中均增加了肿瘤消退，值得在这些HGSOC亚组中进一步研究。
