TTK activates ATR through RPA2 phosphorylation to promote olaparib resistance in ovarian cancer.

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.