Targeting p300 Reverses Acidic Microenvironment-Induced PARP Inhibitor Resistance
Poly(ADP-ribose) polymerase inhibitors (PARPi) are a first-line treatment for epithelial ovarian cancer (EOC) patients, but the development of resistance limits long-term therapeutic efficacy. Tumor acidosis is a hallmark of the tumor microenvironment that has been shown to promote resistance to cancer therapies, suggesting that it may impact PARPi response. Here, we demonstrated that the acidic tumor microenvironment 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 anti-tumor efficacy of PARPi. 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 PARPi and poor overall survival. In patient-derived and syngeneic EOC models, pharmacologic inhibition of p300 synergized with PARPi 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.
Authors
- Wei Zhou (ORCID: https://orcid.org/0000-0001-9607-4490)
- Liping Liao (ORCID: https://orcid.org/0000-0002-8430-1956)
- Benjamin G. Bitler (ORCID: https://orcid.org/0000-0002-5809-5271)
- Andrew V. Kossenkov (ORCID: https://orcid.org/0000-0002-1536-0418)
- Stefanie Flückiger-Mangual
- Hao Nie (ORCID: https://orcid.org/0000-0002-8985-1279)
- Siyu Xia (ORCID: https://orcid.org/0000-0002-4241-4944)
- Janardan N. Gavade (ORCID: https://orcid.org/0000-0002-4452-5699)
- Hsin‐Yao Tang (ORCID: https://orcid.org/0000-0003-1838-018X)
- Dajiang Guo (ORCID: https://orcid.org/0000-0001-5856-5854)
- Timothy Anthony Yap (ORCID: https://orcid.org/0000-0002-2154-3309)
- Michael Soth (ORCID: https://orcid.org/0000-0002-2649-5537)
- Shruthi Sriramkumar (ORCID: https://orcid.org/0000-0003-1308-2546)
- Jinsong Liu (ORCID: https://orcid.org/0000-0002-3239-6658)
- Rugang Zhang (ORCID: https://orcid.org/0000-0002-7255-2360)
- Xu Zhang (ORCID: https://orcid.org/0000-0003-3354-2458)
- Shuai Wu (ORCID: https://orcid.org/0000-0002-3183-5081)
- Yuan Qi (ORCID: https://orcid.org/0000-0001-9718-7593)
- Anil K. Sood (ORCID: https://orcid.org/0000-0003-4242-1762)
- Kang Le (ORCID: https://orcid.org/0009-0004-0279-7815)
- Rafał Zieliński (ORCID: https://orcid.org/0000-0001-5735-9119)
- Chen Wang (ORCID: https://orcid.org/0000-0002-9803-1483)
- K. S. Cheng
- Miriam D. Post
- Yiming Fang (ORCID: https://orcid.org/0009-0002-3141-4209)
- Dorothea Gruber (ORCID: https://orcid.org/0009-0003-9951-3411)
Institutions
- The Wistar Institute (US)
- The University of Texas MD Anderson Cancer Center (US)
- Chinese University of Hong Kong (HK)
- PIQUR Therapeutics (Switzerland) (CH)
- University of Colorado Anschutz Medical Campus (US)
- University of Pennsylvania (US)
- University of Colorado Denver (US)
- Philadelphia University (US)
Publication Details
- Journal
- Cancer Research
- Published
- 2026-07-17
- DOI
- https://doi.org/10.1158/0008-5472.can-26-0834
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00