Fibroblast growth factor receptor 3–Transforming acidic coiled-coil protein 3 fusion protein (FGFR3-TACC3)

The FGFR3-TACC3 fusion protein is a potent oncogenic driver resulting from a chromosomal translocation, most commonly an interstitial duplication on chromosome 4p16.3 (Singh et al., Science, 2012 [1]). This fusion combines the tyrosine kinase domain of Fibroblast Growth Factor Receptor 3 (FGFR3) with the coiled-coil domain of Transforming Acidic Coiled-Coil protein 3 (TACC3), leading to constitutive dimerization and activation of the FGFR3 kinase (Parker et al., J Clin Invest, 2013 [2]). This aberrant signaling bypasses normal regulatory mechanisms to hyperactivate downstream pathways, most notably the PI3K/Akt/mTOR and MAPK/ERK axes, which promote uncontrolled cell growth, survival, and metabolism (Costa et al., Oncotarget, 2016 [3]). FGFR3-TACC3 fusions are frequently identified in various malignancies, including glioblastoma multiforme, urothelial carcinoma, and non-small cell lung cancer (Daly et al., Cancer Discovery, 2017 [4]). Targeting this fusion with selective FGFR inhibitors like erdafitinib has shown clinical efficacy, although resistance often develops through secondary mutations or bypass signaling (Loriot et al., NEJM, 2019 [5]). Understanding the specific reliance of these tumors on Akt/mTOR signaling provides a rationale for combination therapies involving both FGFR and mTOR inhibitors to overcome resistance and enhance therapeutic depth (Di Stefano et al., Clin Cancer Res, 2015 [6]).

Other names

FGFR3-TACC3 fusionFGFR3-TACC3 chimeraFGFR3-TACC3 oncogenic driverF3-T3 fusion

Small molecule inhibitors bind to the ATP-binding pocket of the FGFR3 kinase domain within the fusion protein, preventing autophosphorylation and the subsequent constitutive activation of downstream PI3K/Akt/mTOR and MAPK/ERK signaling pathways (Loriot et al., NEJM, 2019 [5]).