Targeting p300 Reverses Acidic Microenvironment-Induced PARP Inhibitor Resistance.
Acidic tumor microenvironment activates p300, causing a 50% reduction in PARPi effectiveness in epithelial ovarian cancer.
- Why it matters: Overcoming resistance to PARP inhibitors is critical for improving long-term outcomes in ovarian cancer patients, as resistance limits treatment success.
- What they did: The study used CRISPR-Cas9 screening and patient-derived models to show that acidic pH activates an ERK-p300-PARP1 pathway, leading to increased PARP1 acetylation and reduced drug trapping.
- The result: Inhibiting p300 restored PARPi sensitivity and suppressed tumor growth, highlighting p300 as a promising target to counteract microenvironment-driven resistance.