Abstract 4680: Simultaneous DDR1/FGFR inhibition elicits adaptive EGFR/MAPK pathway activation to counteract susceptibility to radiochemotherapy in preclinical glioblastoma models

Abstract GBM cell survival critically depends on cell adhesion molecules like discoidin domain receptor 1 (DDR1) and receptor tyrosine kinases like fibroblast growth factor receptors (FGFR), both of which represent potential therapeutic vulnerabilities. Based on the radiochemosensitizing potential of DDR1 mono-inhibition, we investigated the adaptive response induced by DDR1 deactivation using broad-spectrum kinome analyses. Since FGFR were identified most hyperactive, we examined the efficacy of simultaneous pharmacological DDR1/FGFR inhibition and found enhanced cytotoxicity and radiochemosensitization in a human gliomasphere panel. Subsequent evaluation of DDR1 and FGFR single and dual inhibition in orthotopic, radiochemotherapy-treated GBM mouse models revealed a profound reduction in efficacy for dual as opposed to single inhibition. This was mechanistically underpinned through RNA-seq analyses uncovering strong activation of EGFR/MAPK signaling under DDR1/FGFR deactivation relative to monotherapies. In conclusion, our data evidently show that particularly DDR1 monotherapy effectively augments radiochemotherapy in GBM, while simultaneous DDR1/FGFR inhibition requires more in-depth investigation. Citation Format: Anne Vehlow, Irina Korovina, Olegs Borodins, Nils Cordes. Simultaneous DDR1/FGFR inhibition elicits adaptive EGFR/MAPK pathway activation to counteract susceptibility to radiochemotherapy in preclinical glioblastoma models [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 4680.