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.
View: Text | PDF
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

×

Figure 3

Combination of talazoparib and PD173074 attenuates DNA repair.

Options: View larger image (or click on image) Download as PowerPoint
Combination of talazoparib and PD173074 attenuates DNA repair. (A–C) SUM...
(A–C) SUM149 parental (A), BR#09 (B), and BR#17 (C) cells were treated with 5 μM FGFRi (PD173074, JNJ-42756493, AZD4547) for 4 hours, then further exposed for 1 hour to 100 nM talazoparib (Tala) and 0.01% MMS along with the indicated FGFRis before Western blot analysis. (D and E) BR#17 cells were treated with MMS and the indicated inhibitors for 1 hour, followed by inhibitor treatment after MMS removal. Immunofluorescence images (D) display γH2AX (green) and DNA (blue). Scale bars: 20 μm. Scatterplot (E) shows mean ± SD from 3 independent experiments; scatterplot represents all counted cells. One-way ANOVA with Tukey’s test: *P < 0.05 and **P < 0.001. (F) The indicated cells were treated with 100 nM talazoparib and 0.01% MMS for 1 hour (+MMS), then recovered in fresh medium for 3 hours before comet assay. Scatterplot displays the mean ± SD from 3 experiments; scatterplot includes all cells counted. One-way ANOVA with Tukey’s test: *P < 0.05 and **P < 0.01. Representative comet assay images are shown in Supplemental Figure 5B. (G) BR#09 cells received 0.01% MMS, 100 nM talazoparib, and/or 5 μM PD173074 (alone or combined) for 1 hour before alkaline comet assay. DNA damage (olive moment) was normalized to the talazoparib-treated group. Scatterplot shows mean ± SD from 3 experiments; scatterplot represents all counted cells. One-way ANOVA with Tukey’s test: ***P < 0.001. Representative comet assay images are shown in Supplemental Figure 5C.