FGFR1 Suppresses STING-Mediated Interferon Response in Endocrine Therapy-Resistant Breast Cancer.

UNLABELLED: Fibroblast growth factor receptor 1 (FGFR1) amplification is frequently observed in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer and has been linked to poor response to endocrine therapy. Although FGFR1 has been implicated in therapeutic resistance, its role in regulating interferon (IFN) response in the context of endocrine resistance remains unclear. We investigated whether FGFR1 modulates the IFN response through the cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway in tamoxifen-resistant breast cancer. We employed tamoxifen-resistant ER+ breast cancer cell lines and a tamoxifen-sensitive FGFR1-amplified patient-derived xenograft (PDX) model to examine the impact of FGFR1 inhibition on the IFN response through RNA sequencing, FGFR1 knockdown or pharmacologic inhibition, and functional assays. Clinical relevance was evaluated in breast cancer cohorts. Tamoxifen-resistant cells exhibited increased cytosolic, cGAS-positive double-stranded DNA (dsDNA) foci alongside elevated phosphorylated IRF3 (p-IRF3), indicating constitutive engagement of the cGAS-STING pathway. FGFR1 inhibition resensitized resistant cells to tamoxifen and induced IFN response gene expression, which was further amplified by tamoxifen cotreatment. FGFR1 inhibition similarly potentiated tamoxifen-induced IFN response gene expression in vivo in an FGFR1-amplified PDX model. Mechanistically, FGFR1 knockdown enhanced STING-mediated IFNB1 expression in response to cytosolic DNA. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR1 amplification was associated with poor prognosis specifically in tumors with high STING1 expression. These findings identify FGFR1 as a suppressor of cGAS-STING-mediated IFN response, driven by tamoxifen in ER+ breast cancer. Attenuation of this response may represent a previously unrecognized contribution of FGFR1 to tamoxifen resistance.

SIGNIFICANCE: We identify FGFR1 as a suppressor of tamoxifen-driven IFN response in ER+ breast cancer and propose that attenuation of this response contributes to endocrine resistance. Our findings suggest that FGFR1 amplification combined with high STING1 expression could serve as a prognostic biomarker in trials of FGFR1-targeted therapies.