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 (ETAR), whose overexpression correlated with an unfavourable HG-SOC patient outcomes, predicted a worst prognosis in the homologous recombination proficient subgroup of patients. ETAR 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 ETAR expression. The genetic and pharmacological inhibition of ETAR has the ability to potentiate the efficacy of the PARPi with DDR inhibitors (DDRi) combination, blocking the ETAR-mediated evasion from PARPi-induced apoptosis and DNA damage. Clinically relevant, in PD HG-SOC xenografts, the co-targeting of PARP, ATR, and ETAR effectively suppressed the olaparib-induced ETAR upregulation and enhanced PARPi sensitivity, preventing metastatic dissemination. These results explain a resilience mechanism in which ETAR confers a therapeutic vulnerability that may be leveraged for therapy with ATR and ETAR inhibitors in combination with PARPi, holding the promise of developing new therapeutic strategies less prone to drug resistance.