DDDR-06. Concurrent pharmacological FGFR/DDR1 inhibition diminishes the efficacy of radiochemotherapy in glioblastoma

Abstract The survival of GBM cells critically depends on receptor tyrosine kinases like fibroblast growth factor receptors (FGFR) and cell adhesion molecules like discoidin domain receptor 1 (DDR1), both of which represent potential therapeutic targets. Although adaptive responses to pharmacological inhibitors are known, therapeutic adaptation is often hampered due to a lack of underlying mechanisms. Based on the radiochemosensitizing potential of DDR1 monoinhibition, we investigated the adaptive response induced by DDR1 inactivation using a broad-spectrum kinome analysis (PAMgene technology). Since FGFRs have been identified as the most potently induced tyrosine receptors, we investigated the efficacy of concurrent pharmacological FGFR/DDR1 inhibition and observed increased cytotoxicity and radiochemosensitization in a series of human gliomasphere models. Subsequent evaluation of single and concurrent FGFR and DDR1 inhibition in orthotopic GBM mouse models treated with chemoradiotherapy revealed a significant reduction in the efficacy of simultaneous FGFR/DDR1 inhibition compared to FGFR or DDR1 monotherapy. Mechanistically, RNA sequencing analyses demonstrated that strong activation of EGFR/MAPK signaling with concurrent FGFR/DDR1 inactivation greatly reduced the efficacy of chemoradiotherapy compared to monotherapies. In summary, our data clearly demonstrate that DDR1 monotherapy, in particular, effectively complements chemoradiotherapy in GBM, whereas concurrent FGFR/DDR1 inhibition appears harmful and requires further investigation.