FGFR3-induced Y158 PARP1 phosphorylation promotes PARP inhibitor resistance via BRG1/MRE11-mediated DNA repair in breast cancer models

• Published in: The Journal of clinical investigation Vol. 135; no. 14
• Main Authors: Chen, Mei-Kuang, Yamaguchi, Hirohito, Gao, Yuan, Xia, Weiya, Chang, Jeffrey T., Hsiao, Yu-Chun, Shegute, Tewodros W., Lin, Zong-Shin, Wu, Chen-Shiou, Wang, Yu-Han, Litton, Jennifer K., Ding, Qingqing, Wei, Yongkun, Chu, Yu-Yi, Meric-Bernstam, Funda, Piwnica-Worms, Helen, Arun, Banu, Rodon Ahnert, Jordi, Liu, Jinsong, Yao, Jun, Chang, Wei-Chao, Wang, Hung-Ling, Tapia, Coya, Albarracin, Constance T., Keyomarsi, Khandan, Wang, Shao-Chun, Wang, Ying-Nai, Hortobagyi, Gabriel N., Lin, Chunru, Yang, Liuqing, Yu, Dihua, Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.07.2025
• Subjects: Animals; Cell Line, Tumor; DNA Helicases - genetics; DNA Helicases - metabolism; DNA Repair - drug effects; Drug Resistance, Neoplasm; Female; Humans; Mice; MRE11 Homologue Protein - genetics; MRE11 Homologue Protein - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphorylation - drug effects; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Receptor, Fibroblast Growth Factor, Type 3 - genetics; Receptor, Fibroblast Growth Factor, Type 3 - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Xenograft Model Antitumor Assays; Oncology; Breast cancer; Drug therapy; Protein kinases; Therapeutics
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI173757

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.