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 7

FGFR and PARP inhibitors synergize in breast cancer xenograft models.

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FGFR and PARP inhibitors synergize in breast cancer xenograft models. (A...
(A) Tumor-bearing mice were treated with olaparib and/or AZD4547. The top graph shows BR#09 xenografts (n = 5), and the bottom graph shows BR#17 xenografts (n = 4). Tumor volumes were measured over time and analyzed by 1-way ANOVA with Tukey’s test (mean ± SD; **P < 0.01 and ***P < 0.001). (B) Survival curves corresponding to the mice in A; BR#09 (top) and BR#17 (bottom). (C) Tumor growth in BR#09 (n = 5) and BR#17 (n = 6) xenograft models treated with talazoparib and PD173074, analyzed by 1-way ANOVA with Tukey’s test (mean ± SD; ***P < 0.001). (D) The tumor chunks of TNBC PDX model (BCX.070) were inoculated into the fourth mammary fat pad of female nude mice. Once tumors reached 80–100 mm3, mice were treated orally with vehicle (n = 3), olaparib (n = 4), AZD4547 (n = 4), or the combination (n = 4). Data are presented as the mean ± SEM; 1-way ANOVA with Tukey’s test (***P < 0.001). (E) Blood chemical test from 6 BALB/c mice treated with talazoparib and PD173074. Mean values and individual data points are shown. Dotted lines represent the reference levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood urea nitrogen (BUN) in BALB/c mice.