FGFR3-induced Y158 PARP1 phosphorylation promotes PARP inhibitor resistance via BRG1/MRE11-mediated DNA repair in breast cancer models
Mei-Kuang Chen, … , Dihua Yu, Mien-Chie Hung
Mei-Kuang Chen, … , Dihua Yu, Mien-Chie Hung
Published June 3, 2025
Citation Information: J Clin Invest. 2025;135(14):e173757. https://doi.org/10.1172/JCI173757.
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Research Article Oncology

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

Abstract

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

Mei-Kuang Chen, Hirohito Yamaguchi, Yuan Gao, Weiya Xia, Jeffrey T. Chang, Yu-Chun Hsiao, Tewodros W. Shegute, Zong-Shin Lin, Chen-Shiou Wu, Yu-Han Wang, Jennifer K. Litton, Qingqing Ding, Yongkun Wei, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Jinsong Liu, Jun Yao, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T. Albarracin, Khandan Keyomarsi, Shao-Chun Wang, Ying-Nai Wang, Gabriel N. Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung

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Figure 1

FGFR3 is activated in talazoparib-resistant cells.

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FGFR3 is activated in talazoparib-resistant cells. (A) Colony formation ...
(A) Colony formation of SUM149 parental and BR cells in response to talazoparib. (B) Half-maximal inhibitory concentration (IC50) of TNBC cells in response to talazoparib. Cells were treated with talazoparib for 4 days before cell survival was analyzed by MTT assay. IC50 was calculated using GraphPad Prism 8.0. Histogram shows the mean ± SEM. (Biological repeats: SUM149 n = 5, HCC1806BR n = 4, all other cell lines n = 3.) (C) Talazoparib and olaparib IC50 of SUM149-BR cells according to MTT assay. Fold change (×) of IC50 was compared with that of SUM149 parental cells (SUM). Histogram shows the mean ± SEM (n ≥3). The purple bars represent the cells used in the antibody array analysis in D and E, while the white bars represent the others. (D and E) Antibody arrays of RTK activation in SUM149 parental and SUM149-BR cells. Cells were treated with DMSO or 100 nM talazoparib overnight and harvested for RTK antibody array analysis. (D) The images of RTK antibody arrays in SUM149 parental, BR#09, and BR#17. (E) The signal intensities from all the arrays are shown as heatmaps.