Qi Gonghua, Ma Hanlin, Chen Jingying, Gai Panpan, Teng Kai
Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China.
Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, Jinan, China.
Commun Biol. 2025 Jul 5;8(1):1011. doi: 10.1038/s42003-025-08444-7.
Resistance to poly(ADP‒ribose) polymerase inhibitors (PARPis) remains a significant challenge in ovarian cancer (OC) treatment. TTK protein kinase (TTK) has been implicated in cisplatin resistance in OC, but its role in PARPi resistance remains unclear. In this research, we found that TTK inhibition overcome olaparib resistance in HR-proficient OC cells, whereas TTK promotes olaparib resistance in HR-deficient OC cells. Mechanistically, TTK directly interacts with RPA2, facilitating phosphorylation of its S33 residue to activate the ATR signaling pathway. Knocking down RPA2 increased olaparib sensitivity in OC cells. Additionally, TTK-mediated resistance to olaparib through the RPA2/ATR signaling pathway was confirmed via both in vitro and in vivo models. In conclusion, TTK inhibition overcomes olaparib resistance in HR-proficient OC cells, in part by suppressing RPA2-S33 phosphorylation and attenuating ATR signaling. TTK inhibitors offer a promising strategy to increase the therapeutic efficacy of PARPis in OC patients.
对聚（ADP-核糖）聚合酶抑制剂（PARPis）产生耐药性仍然是卵巢癌（OC）治疗中的一项重大挑战。TTK蛋白激酶（TTK）与OC中的顺铂耐药性有关，但其在PARPi耐药性中的作用仍不清楚。在本研究中，我们发现抑制TTK可克服HR功能正常的OC细胞中的奥拉帕利耐药性，而TTK在HR缺陷的OC细胞中促进奥拉帕利耐药性。机制上，TTK直接与RPA2相互作用，促进其S33残基的磷酸化以激活ATR信号通路。敲低RPA2可增加OC细胞对奥拉帕利的敏感性。此外，通过体外和体内模型均证实了TTK通过RPA2/ATR信号通路介导对奥拉帕利的耐药性。总之，抑制TTK可克服HR功能正常的OC细胞中的奥拉帕利耐药性，部分原因是通过抑制RPA2-S33磷酸化和减弱ATR信号。TTK抑制剂为提高PARPis在OC患者中的治疗效果提供了一种有前景的策略。
