DNA damaging agents boost the transcription of endothelin A receptor in high-grade serous ovarian cancer

The antineoplastic agents, Poly ADP-ribose polymerase (PARP) inhibitors (PARPi) and platinum-based drugs, marked a paradigm shifting in high-grade serous ovarian Cancer (HG-SOC) treatment. Nonetheless, the HG-SOC vulnerability to these agents is challenged by the hyper-activation of adaptive pro-survival pathways. In this study, we report that the endothelin A receptor (ET_AR), whose overexpression correlated with an unfavourable HG-SOC patient outcomes, predicted a worst prognosis in the homologous recombination proficient subgroup of patients. ET_AR levels increased upon treatment with DNA damaging agents, as the PARPi olaparib, or cisplatin in patient-derived (PD) HG-SOC cells and HG-SOC cell lines, regardless of their BRCA1/2 mutational status. Mechanistically, these compounds, inducing the DNA Damage Response (DDR) signalling, including ATM and ATR, leveraged the STAT3-dependent transcriptional machinery to induce ET_AR expression. The genetic and pharmacological inhibition of ET_AR has the ability to potentiate the efficacy of the PARPi with DDR inhibitors (DDRi) combination, blocking the ET_AR-mediated evasion from PARPi-induced Apoptosis and DNA damage. Clinically relevant, in PD HG-SOC xenografts, the co-targeting of PARP, ATR, and ET_AR effectively suppressed the olaparib-induced ET_AR upregulation and enhanced PARPi sensitivity, preventing metastatic dissemination. These results explain a resilience mechanism in which ET_AR confers a therapeutic vulnerability that may be leveraged for therapy with ATR and ET_AR inhibitors in combination with PARPi, holding the promise of developing new therapeutic strategies less prone to drug resistance.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13046-025-03607-0.

ATR; DNA damage response; ETAR; Ovarian cancer; PARPi.