Abstract 6141: FGFR1 promotes endocrine resistance and regulates DNA sensing via STING modulation in hormone receptor-positive breast cancer

Abstract Alterations in the receptor tyrosine kinase Fibroblast Growth Factor Receptor 1 (FGFR1), such as gene amplification and overexpression, are frequently observed in hormone receptor-positive breast cancers, driving aberrant signaling pathways that promote tumor growth, metastasis, drug resistance, and immune evasion. This study investigates the dual role of FGFR1 in mediating endocrine resistance and modulating innate immune sensing via the cGAS-STING pathway and Type 1 interferon (IFN) responses. Our findings reveal a direct link between FGFR1 activity and endocrine resistance in estrogen receptor-positive T47D breast cancer cells. Strikingly, FGFR1 expression negatively correlates with Type 1 IFN responses in these cells, while endocrine-resistant cells exhibit upregulated STING expression at both mRNA and protein levels. Pharmacological inhibition of FGFR1 using erdafitinib or shRNA-mediated silencing enhances the expression of interferon-stimulated genes (ISGs) by activating the STING-TBK1-IRF3 signaling axis. Mechanistically, we identified that constitutive FGFR1 kinase activity activates AKT, which suppresses STING-TBK1-mediated Type 1 IFN responses as a negative feedback mechanism. In vivo, the combination of FGFR1 inhibition endocrine therapy led to tumor regression in a luminal patient-derived xenograft (PDX) model, driven by an enhanced tumor-intrinsic Type 1 IFN response. These results suggest that FGFR1 acts as an innate immune checkpoint, enabling tumor cells to suppress STING mediated Type 1 IFN response and evade antitumor immunity in hormone receptor-positive breast cancer. Targeting FGFR1 may, therefore, represent a promising strategy to overcome endocrine resistance and restore immune surveillance in this context. Citation Format: Sushil Dhakal, Torbjørn Amundsen Lien, Phuong Vu, Helene Midtun Flatekvål, Jens Henrik Norum, Therese Sørlie. FGFR1 promotes endocrine resistance and regulates DNA sensing via STING modulation in hormone receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6141.