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 2

Synergy between PARPis and FGFRis is independent of BRCA1 expression.

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Synergy between PARPis and FGFRis is independent of BRCA1 expression. (A...
(A) BR#09 and BR#17 cells were treated with talazoparib (Tala) and PD173074 (PD), either alone or in combination (Combo), at the concentrations indicated for 10–12 days, and then cells were fixed for the colony formation assay. The number of colonies formed was normalized to that in the control group (not treated with talazoparib and PD173074), and the mean ± SD from 3 independent experiments is shown in the histogram. *P < 0.05, **P < 0.01, and ***P < 0.001. ANOVA was used for statistical comparisons. Representative images of colony formation are shown in Supplemental Figure 4, C and D. (B and C) Combination index (CI) of the talazoparib and PD173074 combination or the olaparib and AZD4547 combination in SUM149-BR (B), BT549 (C), and MDA-MB-157 (C) cells. Cells were treated with various concentrations of talazoparib and PD173074 or olaparib and AZD4547 for 4 days before cell survival was measured by MTT assay and the CI was calculated by CompuSyn. Fa, fraction affected. (D) Immunofluorescence of SUM149 parental, BR#09, and BR#17 cells staining for DAPI (DNA), RAD51 foci (homologous repair), and γ-H2AX foci (double-strand breaks) after 24 hours of 50 nM talazoparib treatment. Scale bars: 20 μm. (E) BRCA1 was knocked down with 2 different shRNAs (shBRCA1-1 and shBRCA1-3) in BR#09 and BR#17 cells. Moreover, BRCA1 was re-expressed in BR#09 and BR#17 shBRCA1-3 cells (WT-BRCA1). These cells, including the control cells (LKO.1), were treated with various concentrations of talazoparib and PD173074 combination, and the CI values were determined. The expression of BRCA1 was determined by Western blot, and the results are shown in Supplemental Figure 4, G and H.