ATPS-37: THERAPEUTIC VULNERABILITIES AND RESISTANCE MECHANISMS FOR THE PRECISION MEDICINE OF GLIOBLASTOMA

Gene fusions generated by chromosomal translocations are the best examples of success for targeted cancer therapy. Our work in malignant glioma identified the first examples of highly oncogenic and recurrent gene fusions that result in constitutive activation of receptor tyrosine kinase genes (FGFR, EGFR and NTRK). Among them, FGFR-TACC is the addicting gene fusion with highest therapeutic value. It is also the gene fusion most frequently represented across other cancer types. Thus, elucidating how FGFR-TACC drives oncogenesis and mechanisms of resistance to FGFR inhibitors are crucial questions with fundamental general implications. By using a combination of unbiased mass spectrometry and functional validation experiments, we have recently identified the tyrosine phosphorylation targets of FGFR-TACC fusions in glioblastoma. We have also generated an inducible and reversible mouse model for FGFR-TACC-mediated tumorigenesis. These mice revealed a strong tumor initiation capacity by FGFR-TACC fusions in the nervous system. They also exposed strict dependency of tumor cells to continuous expression of the FGFR-TACC fusion gene. The mouse model has also allowed us to establish the significance of the new signaling pathways and determine the mechanisms of recurrence of FGFR-TACC-initiated tumors following fusion ablation. The integrated availability of FGFR-TACC substrates and the reversible mouse model of FGFR-TACC-driven tumors are elucidating the mechanisms of resistance triggered by chronic targeting of the fusion gene. The model applied to FGFR-TACC is now being extended to EGFR and NTRK gene fusions to determine similarities and differences and assign accurate therapeutic value to individual chromosomal translocations. Together with the screening and personalized validation paradigm recently completed for the identification, characterization and targeting of FGFR-TACC fusions in patients malignant glioma, the new information will allow us to accurately predict strength of evidence of oncogenic activity and size of anticipated targeting effect for the selection of any “druggable” genetic alteration in GBM patients.