Targeting p300 Reverses Acidic Microenvironment–Induced PARP Inhibitor Resistance

Abstract Poly (ADP-ribose) polymerase inhibitors (PARPi) are a first-line treatment for patients with epithelial ovarian cancer (EOC), but the development of resistance limits long-term therapeutic efficacy. Tumor acidosis is a hallmark of the tumor microenvironment (TME) that has been shown to promote resistance to cancer therapies, suggesting that it may affect PARPi responses. In this study, we demonstrated that the acidic TME drives a p300-dependent mechanism of PARPi resistance in EOC. Pathologically acidic pH enhanced DNA damage repair, reduced PARPi-induced PARP1 trapping, and attenuated the antitumor efficacy of PARPis. A CRISPR–Cas9 screen identified p300 as a druggable mediator of acidosis-induced PARPi resistance. Mechanistically, acidic pH activated an ERK–p300–PARP1 signaling axis that acetylated PARP1 at lysine 505 (PARP1 K505Ac), thereby alleviating PARPi-mediated PARP1 trapping and DNA damage. Elevated PARP1 K505Ac was associated with clinical resistance to PARPis and poor overall survival. In patient-derived and syngeneic EOC models, pharmacologic inhibition of p300 synergized with PARPis to suppress tumor growth. Together, these findings identify p300 as a key mediator of acidosis-induced PARPi resistance and a promising therapeutic target to enhance PARPi efficacy. Significance: Tumor acidosis drives PARP inhibitor resistance by promoting p300-dependent acetylation of PARP1, which can be effectively targeted in preclinical models to reverse resistance and improve the therapeutic efficacy of PARP inhibitors.