Targeting p300 Reverses Acidic Microenvironment-Induced PARP Inhibitor Resistance.

Acidic tumor microenvironment induces PARPi resistance in epithelial ovarian cancer through p300-dependent mechanisms.

• Why it matters: Tumor acidosis is common in the microenvironment and is known to promote resistance to cancer therapies, but its role in PARPi resistance in EOC was unclear.
• What they did: A CRISPR-Cas9 screen identified p300 as a druggable mediator; experiments showed acidic pH activates an ERK-p300-PARP1 axis, increasing PARP1 acetylation and reducing PARPi effectiveness.
• The result: Inhibiting p300 enhances PARPi response in patient-derived and mouse models, suggesting p300 targeting could improve long-term treatment outcomes for EOC patients.