Increased efficacy of PARP inhibitors against cisplatin-sensitive and -resistant ovarian cancer cells mediated via ATR and ATM inhibition

PARP inhibitors (PARPi) are approved for the treatment of platinum-based therapy-responsive ovarian cancer. However, this severely restricts their therapeutic potential, since there is only limited knowledge on the efficacy of PARPi in platinum drug-resistant ovarian cancer cells. Here, we studied three approved PARPi, niraparib, olaparib, and rucaparib in three ovarian cancer cell lines and their cisplatin-resistant sublines. Complex response profiles demonstrated that cisplatin resistance was not consistently associated with cross-resistance to PARPi. The combination of PARPi with inhibitors of relevant DNA damage response kinases which are potentially involved in PARPi resistance, such as ATR, ATM, CHK1, and WEE1 again resulted in complex activity patterns, but also identified ATR and ATM as the most promising targets for increasing PARPi activity. Cell adhesion-mediated resistance via collagen I is known to mediate cisplatin resistance. Here, we show that collagen I can also mediate PARPi resistance, which can also be tackled by ATR and ATM inhibition in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines. In conclusion, our findings revealed complex, cell line-specific PARPi response profiles. This complexity is in line with other studies investigating drug-resistant cancer cell lines and with the complex evolutionary processes in tumors from cancer patients. Notably, cisplatin resistance was not directly correlated with PARPi resistance, and ATM and ATR inhibitors can increase PARPi activity against cisplatin-sensitive and -resistant ovarian cancer cells. Moreover, we demonstrated for the first time that cell adhesion-mediated resistance can contribute to PARPi resistance, which can also be alleviated by ATR and ATM.