Faculty, Staff and Student Publications

Publication Date

7-15-2025

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI173757

PMID

40460005

PMCID

PMC12259256

PubMedCentral® Posted Date

5-29-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Poly(ADP-ribose) Polymerase Inhibitors, Poly (ADP-Ribose) Polymerase-1, Female, DNA Helicases, Animals, Drug Resistance, Neoplasm, Mice, Nuclear Proteins, Cell Line, Tumor, Transcription Factors, Triple Negative Breast Neoplasms, Receptor, Fibroblast Growth Factor, Type 3, Phosphorylation, MRE11 Homologue Protein, DNA Repair, Xenograft Model Antitumor Assays, Neoplasm Proteins, Oncology, Therapeutics, Breast cancer, Drug therapy, Protein kinases

Published Open-Access

yes

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