The landscape of FGFR-TACC fusion in adult glioblastoma: From bench to bedside

Abstract

Glioblastoma (GBM) is a lethal central nervous system tumor, characterized by extensive genomic alterations and high intra-tumoral heterogeneity. Gene fusions, derived from chromosomal translocations, deletions, and inversions, were increasingly recognized as key carcinogenic events, with the highest frequency of FGFR-TACC fusion in glioblastoma. As reported, FGFR3-TACC3 fusion mostly coexists with wild-type IDH status, and associates with better prognosis. Mechanistically, FGFR3-TACC3 fusions can constitutively activate non-canonical FGFR downstream pathways, induce aneuploidy, and participate in mitochondrial metabolism, thereby promoting cell proliferation and tumorigenesis. These functions, whether based on FGFR3 phosphorylation or not, are predominantly attributed to the specific domain of TACC3 that involved in regulating the localization and activation of fusion products. Several preclinical studies and clinical trials are being performed to evaluate the efficacy and safety of the FGFR-TACC fusion as a personalised therapeutic target, including the treatments with tyrosine kinase inhibitors, metabolic inhibitors, HSP90 inhibitors, coiled-coil peptide-mimetics, and targeted protein degraders. A subset of populations with FGFR-TACC-positive glioblastoma, after refined molecular screening strategies, may benefit from targeted therapies. Despite major progress in biotechnology, our understanding on the role of fusion events in glioblastoma represented by the FGFR-TACC is still in its infancy. Here, we highlight recent progress on FGFR-TACC fusion in human glioblastoma, emphasizing their molecular mechanisms and potential clinical value.