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

• Published in: The Journal of clinical investigation Vol. 135; no. 14
• Main Authors: Chen, Mei-Kuang, Yamaguchi, Hirohito, Gao, Yuan, Xia, Weiya, Chang, Jeffrey T., Hsiao, Yu-Chun, Shegute, Tewodros W., Lin, Zong-Shin, Wu, Chen-Shiou, Wang, Yu-Han, Litton, Jennifer K., Ding, Qingqing, Wei, Yongkun, Chu, Yu-Yi, Meric-Bernstam, Funda, Piwnica-Worms, Helen, Arun, Banu, Rodon Ahnert, Jordi, Liu, Jinsong, Yao, Jun, Chang, Wei-Chao, Wang, Hung-Ling, Tapia, Coya, Albarracin, Constance T., Keyomarsi, Khandan, Wang, Shao-Chun, Wang, Ying-Nai, Hortobagyi, Gabriel N., Lin, Chunru, Yang, Liuqing, Yu, Dihua, Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.07.2025
• Subjects: 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; Oncology; Breast cancer; Drug therapy; Protein kinases; Therapeutics

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...