Low physiological pH drives P300 mediated acetylation of PARP1 and promotes PARP inhibitor resistance

Resistance to PARP inhibitors (PARPi) is a major clinical obstacle in epithelial ovarian carcinoma (EOC). Intrinsic and acquired PARPi resistance ultimately limit therapeutic efficacy and contribute to patient mortality. Despite multiple reported mechanisms of PARPi resistance, few studies have defined the contribution of the tumor microenvironment (TME) in modulating PARPi response. Here, we demonstrate that the acidic TME, commonly observed in EOC, drives a novel mechanism of PARPi resistance. In multiple in vitro and in vivo models, a physiologically low pH of 6.5 is sufficient to enhance DNA damage repair, reduce PARPi-mediated PARP trapping, and attenuate PARPi-mediated anti-tumor efficacy. 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 identified an ERK1/2-p300-PARP1 signaling axis activated under low pH, which alleviates PARPi-induced PARP1 trapping and associated DNA damage by directly acetylating PARP1. In primary human tumors, elevated PARP1 acetylation significantly correlates with poorer overall survival and PARPi resistance. In multiple in vivo patient-derived and syngeneic EOC models, novel p300 bromodomain inhibitors, TT125-802 and IACS-16559, synergize with PARP inhibitors (olaparib or saruparib) to inhibit the growth of therapy-resistant tumors. Together, our findings establish p300 as a promising therapeutic target for overcoming acidosis-driven PARPi resistance.