FGFR3-induced Y158 PARP1 phosphorylation promotes PARP inhibitor resistance via BRG1/MRE11-mediated DNA repair in breast cancer models
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 ac...
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| Published in | The Journal of clinical investigation Vol. 135; no. 14 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Language | English |
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American Society for Clinical Investigation
15.07.2025
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| 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. |
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| AbstractList | 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.
FGFR3 activation promotes PARP inhibitor resistance in triple negative breast cancer, which can be reversed by the combination of FGFR inhibitors and PARP inhibitors. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) 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 (FGFRi) with PARPi. 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/MRE11 axis, suggesting that PARP1 p-Y158 is a biomarker for PARPi resistance that can be overcome by combining FGFRi with PARPi.Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) 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 (FGFRi) with PARPi. 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/MRE11 axis, suggesting that PARP1 p-Y158 is a biomarker for PARPi resistance that can be overcome by combining FGFRi with PARPi. 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. |
| Author | Hsiao, Yu-Chun Hung, Mien-Chie Wang, Yu-Han Litton, Jennifer K. Hortobagyi, Gabriel N. Keyomarsi, Khandan Wang, Ying-Nai Chen, Mei-Kuang Xia, Weiya Yang, Liuqing Liu, Jinsong Wang, Shao-Chun Lin, Zong-Shin Yamaguchi, Hirohito Chang, Jeffrey T. Yao, Jun Ding, Qingqing Chu, Yu-Yi Albarracin, Constance T. Piwnica-Worms, Helen Arun, Banu Lin, Chunru Yu, Dihua Gao, Yuan Wei, Yongkun Wang, Hung-Ling Meric-Bernstam, Funda Rodon Ahnert, Jordi Wu, Chen-Shiou Chang, Wei-Chao Tapia, Coya Shegute, Tewodros W. |
| AuthorAffiliation | 8 Department of Breast Medical Oncology, Division of Cancer Medicine 11 Department of Breast Surgical Oncology, Division of Surgery 5 Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China 12 Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, and 13 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan 9 Department of Anatomic Pathology, Division of Pathology and Laboratory Medicine 2 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 7 Department of Bioinformatics and Computational Biology 1 Department of Molecul |
| AuthorAffiliation_xml | – name: 11 Department of Breast Surgical Oncology, Division of Surgery – name: 1 Department of Molecular and Cellular Oncology and – name: 4 Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan – name: 9 Department of Anatomic Pathology, Division of Pathology and Laboratory Medicine – name: 10 Department of Investigational Cancer Therapeutics – name: 2 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA – name: 3 Institue of Cell Biology, College of Life Sciences, and – name: 5 Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China – name: 6 Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA – name: 8 Department of Breast Medical Oncology, Division of Cancer Medicine – name: 7 Department of Bioinformatics and Computational Biology – name: 12 Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, and – name: 13 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA |
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| Keywords | Oncology Breast cancer Drug therapy Protein kinases Therapeutics |
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| Snippet | Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are used to treat BRCA-mutated (BRCAm) cancer patients; however, resistance has been observed.... Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are used to treat BRCA-mutated (BRCAm) cancer patients; however, resistance has been observed. Therefore,... Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are used to treat BRCA -mutated (BRCAm) cancer patients; however, resistance has been observed.... |
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| SubjectTerms | Animals Cell Line, Tumor DNA Helicases - genetics DNA Helicases - metabolism DNA Repair - drug effects Drug Resistance, Neoplasm Female Humans Mice MRE11 Homologue Protein - genetics MRE11 Homologue Protein - metabolism Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism Phosphorylation - drug effects Poly (ADP-Ribose) Polymerase-1 - genetics Poly (ADP-Ribose) Polymerase-1 - metabolism Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Receptor, Fibroblast Growth Factor, Type 3 - genetics Receptor, Fibroblast Growth Factor, Type 3 - metabolism Transcription Factors - genetics Transcription Factors - metabolism Triple Negative Breast Neoplasms - drug therapy Triple Negative Breast Neoplasms - genetics Triple Negative Breast Neoplasms - metabolism Triple Negative Breast Neoplasms - pathology Xenograft Model Antitumor Assays |
| Title | FGFR3-induced Y158 PARP1 phosphorylation promotes PARP inhibitor resistance via BRG1/MRE11-mediated DNA repair in breast cancer models |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/40460005 https://www.proquest.com/docview/3215571825 https://pubmed.ncbi.nlm.nih.gov/PMC12259256 |
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