FGFR3-induced Y158 PARP1 phosphorylation promotes PARP inhibitor resistance via BRG1/MRE11-mediated DNA repair in breast cancer models
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are used to treat BRCA-mutated (BRCAm) cancer patients; however, resistance has been observed. Therefore, biomarkers to indicate PARPi resistance and combination therapy to overcome that are urgently needed. We identified a high prevalence of activated FGF receptor 3 (FGFR3) in BRCAm triple-negative breast cancer (TNBC) cells with intrinsic and acquired PARPi resistance. FGFR3 phosphorylated PARP1 at tyrosine 158 (Y158) to recruit BRG1 and prolong chromatin-loaded MRE11, thus promoting homologous recombination (HR) to enhance PARPi resistance. FGFR inhibition prolonged PARP trapping and synergized with PARPi in vitro and in vivo. High-level PARP1 Y158 phosphorylation (p-Y158) positively correlated with PARPi resistance in TNBC patient-derived xenograft models, and in PARPi-resistant TNBC patient tumors. These findings reveal that PARP1 p-Y158 facilitates BRG1-mediated HR to resolve the PARP-DNA complex, and PARP1 p-Y158 may indicate PARPi resistance that can be relieved by combining FGFR inhibitors (FGFRis) with PARPis. In summary, we show that FGFRi restores PARP trapping and PARPi antitumor efficacy in PARPi-resistant breast cancer by decreasing HR through the PARP1 p-Y158/BRG1/MER11 axis, suggesting that PARP1 p-Y158 is a biomarker for PARPi resistance that can be overcome by combining FGFRis with PARPis.
Authors
- Chunru Lin (ORCID: https://orcid.org/0000-0002-6473-8229)
- Jeffrey T. Chang (ORCID: https://orcid.org/0000-0002-4578-5636)
- Jun Yao (ORCID: https://orcid.org/0000-0003-1418-3576)
- Qingqing Ding (ORCID: https://orcid.org/0000-0001-7238-7644)
- Jennifer K. Litton (ORCID: https://orcid.org/0000-0001-8390-4985)
- Banu Arun (ORCID: https://orcid.org/0000-0002-5475-8509)
- Gabriel N. Hortobágyi (ORCID: https://orcid.org/0000-0002-4873-4412)
- Shao‐Chun Wang (ORCID: https://orcid.org/0000-0002-5477-1682)
- Jordi Rodón (ORCID: https://orcid.org/0000-0001-6467-3632)
- Constance T. Albarracin (ORCID: https://orcid.org/0000-0002-1236-7315)
- Dihua Yu (ORCID: https://orcid.org/0000-0001-6231-9381)
- Khandan Keyomarsi (ORCID: https://orcid.org/0000-0002-5440-0849)
- Liuqing Yang (ORCID: https://orcid.org/0000-0002-6518-474X)
- Ying‐Nai Wang (ORCID: https://orcid.org/0000-0002-5275-6729)
- Hung-Ling Wang
- Jinsong Liu (ORCID: https://orcid.org/0000-0002-3239-6658)
- Helen Piwnica‐Worms (ORCID: https://orcid.org/0000-0003-4210-6738)
- Funda Meric‐Bernstam (ORCID: https://orcid.org/0000-0001-6816-6072)
- Mien‐Chie Hung (ORCID: https://orcid.org/0000-0003-4317-4740)
- Hirohito Yamaguchi (ORCID: https://orcid.org/0000-0003-0425-916X)
- Mei‐Kuang Chen (ORCID: https://orcid.org/0000-0001-8027-8990)
- Yu‐Chun Hsiao (ORCID: https://orcid.org/0000-0002-6571-3584)
- Zong-Shin Lin (ORCID: https://orcid.org/0000-0003-3365-1240)
- Yuan Gao (ORCID: https://orcid.org/0000-0003-2224-5538)
- Coya Tapia
- Chen-Shiou Wu
- Yu-Yi Chu
- Wei-Chao Chang
- Yongkun Wei (ORCID: https://orcid.org/0000-0001-8998-5333)
- Yu-Han Wang
- Weiya Xia
- Tewodros W. Shegute
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Shanghai Jiao Tong University (CN)
- China Medical University (TW)
- Breast Cancer Research Foundation (US)
- Shaikh Khalifa Medical City (AE)
- XinHua Hospital (CN)
- Breast Cancer Care (GB)
- Advanced Cancer Therapeutics (US)
- Breast Center (CH)
- Analatom (United States) (US)
- Institute of Cell Biology (UA)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-05-29
- DOI
- https://doi.org/10.1172/jci173757
- Citations
- 4
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 4.18
Funders
- Breast Cancer Research Foundation
- Pfizer
- Ministry of Health and Welfare
- Taiho Pharmaceutical
- Society for Immunotherapy of Cancer
- National Comprehensive Cancer Network
- China Medical University Hospital
- Ministry of Education, India
- China Scholarship Council
- National Health Research Institutes
- China Medical University
- National Science and Technology Council
- National Institutes of Health
- Genentech
- University of Texas MD Anderson Cancer Center
- National Cancer Institute
- Division of Materials Research