FGFR3-TACC3 fusion in solid tumors: mini review

Abstract

Fibroblast growth factor receptors (FGFR) are transmembrane kinase proteins with growing importance in cancer biology given the frequency of molecular alterations and vast interface with multiple other signaling pathways. Furthermore, numerous FGFR inhibitors in clinical development demonstrate the expanding therapeutic relevance of this pathway. Indeed, results from early phase clinical trials already indicate that a subset of patients with advanced tumors derive benefit from FGFR targeted therapies. FGFR gene aberrations and FGFR gene rearrangements are relatively rare in solid malignancies. The recently described FGFR3-TACC3 fusion protein has a constitutively active tyrosine kinase domain and promotes aneuploidy. We summarize the prevalence data on FGFR3-TACC3 fusions among different histological tumor types and the preliminary evidence that this rearrangement represents a targetable molecular aberration in some patients with solid tumors.

Keywords: FGFR3-TACC3 fusion; aneuploidy; glioblastoma multiforme; non-small cell lung cancer; phosphatidylinositol 3-Kinase (PI3K).

Figure 1

A. Fibroblast growth factor receptor (FGFR) has intra-cellular tyrosine kinase activity triggered by fibroblast growth factor (FGF) ligand. Its activation leads to FGFR transphosphorylation and activation of protein of ras oncogene (RAS)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-Kinase (PI3K) signaling pathways. B. Fibroblast growth factor receptor3-transforming acidic coiled-coil containing protein 3(FGFR3-TACC3) fusion protein harbors constitutively activated tyrosine kinase domain, which activates mitogen-activated protein kinase (MAPK) pathway. Also, FGFR3-TACC3 localizes to mitotic spindle poles, induces mitotic, chromosomal segregation defects and triggers aneuploidy.

Figure 2. FGFR3-TACC3 gene fusion

Tandem duplication and insertion leads the fusion of the tyrosine kinase domain of FGFR3 to the TACC domain of TACC3.