FGFR3TACC3

FGFR3-TACC3 is an oncogenic gene fusion resulting from an intrachromosomal rearrangement that joins the N-terminal portion of FGFR3 to the C-terminal portion of TACC3. The fusion preserves FGFR3’s kinase domain and provides a TACC3-derived coiled-coil–mediated dimerization domain, producing a constitutively active receptor tyrosine kinase.

Mechanistically, the TACC3 segment promotes ligand-independent dimerization of the FGFR3 kinase, leading to persistent phosphorylation and activation of downstream signaling pathways such as MAPK/ERK and PI3K/AKT. This aberrant signaling supports uncontrolled cell proliferation, survival, and may affect mitotic processes through TACC3’s role in spindle function.

The FGFR3-TACC3 fusion was first described in glioblastoma and has since been reported in other solid tumors, including urothelial carcinoma and, less commonly, non-small cell lung cancer and breast cancer. It is regarded as a relatively rare but potentially actionable oncogenic driver, typically arising from intrachromosomal rearrangements on chromosome 4.

Detection of FGFR3-TACC3 relies on sequencing-based approaches. RNA sequencing can identify the fusion transcript, while DNA-based methods can detect the underlying rearrangement; RT-PCR validation is often used. Fluorescence in situ hybridization and immunohistochemistry are less routinely used for routine fusion detection.

Therapeutically, FGFR inhibitors have shown activity in tumors harboring the FGFR3-TACC3 fusion, with reports of responses in case studies and early clinical trials. Agents such as erdafitinib and other FGFR inhibitors are being explored in FGFR3-TACC3–positive cancers, though responses vary with tumor type and coexisting alterations. Ongoing research seeks to define the fusion’s prognostic value and the breadth of its therapeutic sensitivity.