DDDR-06. Concurrent pharmacological FGFR/DDR1 inhibition diminishes the efficacy of radiochemotherapy in glioblastoma
Year: 2025
Type: conference-abstract
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.
Source: Neuro-Oncology
Institution: Technische Universität Dresden
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416140992
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