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ResearchIn-Press PreviewOncology Open Access | 10.1172/JCI173757

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

Mei-Kuang Chen,1 Hirohito Yamaguchi,1 Yuan Gao,1 Weiya Xia,1 Jeffrey T. Chang,2 Yu-Chun Hsiao,3 Tewodros W. Shegute,3 Zong-Shin Lin,3 Chen-Shiou Wu,3 Yu-Han Wang,1 Jennifer K. Litton,4 Qingqing Ding,5 Yongkun Wei,1 Yu-Yi Chu,1 Funda Meric-Bernstam,6 Helen Piwnica-Worms,7 Banu Arun,4 Jordi Rodon Ahnert,6 Jinsong Liu,5 Jun Yao,1 Wei-Chao Chang,3 Hung-Ling Wang,3 Coya Tapia,6 Constance T. Albarracin,5 Khandan Keyomarsi,7 Shao-Chun Wang,3 Ying-Nai Wang,1 Gabriel N. Hortobagyi,4 Chunru Lin,1 Liuqing Yang,1 Dihua Yu,1 and Mien-Chie Hung3

1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America

3Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Mo, China Medical University, Taichung, Taiwan

4Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

5Department of Anatomic Pathology, Division of Pathology and Laboratory Medi, The University of Texas MD Anderson Cancer Center, Houston, United States of America

6Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America

7Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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Published June 3, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI173757.
Copyright © 2025, Chen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 3, 2025 - Version history
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Abstract

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.

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