FGFR3-induced Y158 PARP1 phosphorylation promotes PARP inhibitor resistance via BRG1/MRE11-mediated DNA repair in breast cancer models
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
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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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 6

PARP1 Y158 phosphorylation enhances the recruitment of BRG1 and MRE11 on chromatin.

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PARP1 Y158 phosphorylation enhances the recruitment of BRG1 and MRE11 on...
(A) BR#09 cells expressing PARP1WT, PARP1Y158D, or PARP1Y158F were treated as described in Figure 5A and harvested at different time points as indicated. Then, chromatin fractions were isolated and subjected to Western blot analysis. Chromatin-bound BRG1 and MRE11 signal intensities were normalized to histone H3 and compared with those of the cells at the beginning of DNA repair (0 minutes after releasing from talazoparib and MMS). Graphs of quantification of BRG1 and MRE11 compared with H3 are shown below. (B) BR#09 cells expressing HA-PARP1 wild type or mutants were treated with 100 nM talazoparib and 0.01% MMS for 1 hour and subjected to immunoprecipitation with anti-HA or control IgG, followed by Western blot with the indicated antibodies. (C) BR#17 cells were cultured in the presence of 100 nM talazoparib, 2 μM PD173074, 100 nM BRGi, or their combination for 8 days, and cell viability was assessed by colony formation assay. Statistical significance was determined by 1-way ANOVA with Tukey’s test (a vs. b or c, b vs. c: P < 0.001). (D) The proposed model of FGFR3-mediated PARPi resistance via HR repair regulated by the FGFR3/PARP1/BRG1 complex.