Nair Jayakumar, Huang Tzu-Ting, Murai Junko, Haynes Brittany, Steeg Patricia S, Pommier Yves, Lee Jung-Min
Women's Malignancies Branch, National Institutes of Health, Bethesda, 20892, MD, USA.
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, USA.
Oncogene. 2020 Aug;39(33):5520-5535. doi: 10.1038/s41388-020-1383-4. Epub 2020 Jul 9.
High grade serous ovarian cancer (HGSOC) is a fatal gynecologic malignancy in the U.S. with limited treatment options. New therapeutic strategies include targeting of the cell cycle checkpoints, e.g., ATR and CHK1. We recently reported a promising clinical activity of the CHK1 inhibitor (CHK1i) prexasertib monotherapy in BRCA wild-type (BRCAwt) HGSOC patients. In this study, biopsies of treated patients and cell line models were used to investigate possible mechanisms of resistance to CHK1i. We report that BRCAwt HGSOC develops resistance to prexasertib monotherapy via a prolonged G2 delay induced by lower CDK1/CyclinB1 activity, thus preventing cells from mitotic catastrophe and cell death. On the other hand, we noted CHK1's regulation on RAD51-mediated homologous recombination (HR) repair was not altered in CHK1i-resistant cells. Therefore, CHK1i sensitizes CHK1i-resistant cells to DNA damaging agents such as gemcitabine or hydroxyurea by inhibition of HR. In summary, our results demonstrate new mechanistic insights of functionally distinct CHK1 activities and highlight a potential combination treatment approach to overcome CHK1i resistance in BRCAwt HGSOC.
高级别浆液性卵巢癌（HGSOC）是美国一种致命的妇科恶性肿瘤，治疗选择有限。新的治疗策略包括靶向细胞周期检查点，例如ATR和CHK1。我们最近报道了CHK1抑制剂（CHK1i）普瑞昔替尼单药治疗在BRCA野生型（BRCAwt）HGSOC患者中具有有前景的临床活性。在本研究中，使用治疗患者的活检样本和细胞系模型来研究对CHK1i耐药的可能机制。我们报告，BRCAwt HGSOC通过由较低的CDK1/细胞周期蛋白B1活性诱导的延长的G2期延迟对普瑞昔替尼单药治疗产生耐药性，从而防止细胞发生有丝分裂灾难和细胞死亡。另一方面，我们注意到在对CHK1i耐药的细胞中，CHK1对RAD51介导的同源重组（HR）修复的调节未改变。因此，CHK1i通过抑制HR使对CHK1i耐药的细胞对吉西他滨或羟基脲等DNA损伤剂敏感。总之，我们的结果证明了功能不同的CHK1活性的新机制见解，并突出了一种潜在的联合治疗方法来克服BRCAwt HGSOC中对CHK1i的耐药性。
