Low physiological pH drives P300-mediated acetylation of PARP1 and promotes PARP inhibitor resistance [Cut & Run]

Resistance to PARP inhibitors (PARPi) remains a major clinical obstacle in epithelial ovarian carcinoma (EOC), ultimately limiting therapeutic efficacy and contributing to patient mortality. Here, we demonstrate that the acidic tumor microenvironment drives a novel mechanism of PARPi resistance. Decreasing the pH is sufficient to reduce PARPi anti-tumor efficacy in multiple in vitro and in vivo EOC models. Through three independent, epigenetically focused CRISPR/Cas9 screens conducted under low pH conditions, we identified p300 as a druggable target for overcoming pH-induced PARPi resistance. Mechanistically, in an unbiased functional proteomic evaluation we uncovered an ERK1/2–p300–PARP1 signaling axis activated under low pH, which alleviates PARPi-induced PARP1 trapping by promoting PARP1 K505 acetylation and thereby reducing replication fork collapse and associated DNA damage and driving PARPi resistance. Notably, in multiple in vivo patient-derived and syngeneic EOC models, two novel p300 bromodomain inhibitors, IACS-16559 and TT125-802, restore sensitivity to PARPi. Together, our findings establish p300 as a promising therapeutic target for overcoming pH-driven PARPi resistance in EOC.