FGFR-TACC3

FGFR3-TACC3 fusion protein activates oxidative phosphorylation and mitochondrial biogenesis^[1]. FGFR3-TACC3 retains FGFR tyrosine kinase activity and incorporates the TACC3 coiled-coil domain, thereby driving oncogenic signaling in glioblastoma^[2]. Mechanistically, the fusion protein localizes to mitotic spindle poles and induces chromosome segregation defects and aneuploidy; inhibition of FGFR kinase activity corrects aneuploidy and prolongs survival in mice with intracranial tumors^[2]. FGFR3-TACC3 evades miR-99a regulation, leading to enhanced fusion gene expression and promoting glioblastoma cell proliferation and tumor progression, whereas wild-type FGFR3 is non-tumorigenic even when overexpressed^[3]. Compared to related fusions such as FGFR1-TACC1, FGFR3-TACC3 is associated with uniform FGFR3 expression in IDH-wild-type gliomas and is mutually exclusive with IDH1/2 mutations and EGFR amplification^[4]. The FGFR inhibitor JNJ-42756493 suppresses the growth of FGFR3-TACC3-positive glioma cells both in vitro and in vivo, and has resulted in clinical improvement, stable disease, or minor remission in two patients^[4].