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Diffuse Gliomas with FGFR3-TACC3 Fusions: Oncogenic Mechanisms, Hallmarks, and Therapeutic Perspectives
Alberto Picca1,2, Giulio Sansone3, Orazio Santo Santonocito4
1Paris Brain Institute (ICM), Sorbonne Université, Inserm, CNRS, UMR S 1127, 75013 Paris, France.
Abstract:
In 2012, whole-transcriptome sequencing analysis led to the discovery of recurrent fusions involving the FGFR3 and TACC3 genes as the main oncological driver in a subset of human glioblastomas. Since then, FGFR3-TACC3 fusions have been identified in several other solid cancers. Further studies dissected the oncogenic mechanisms of the fusion protein and its complex interplay with cancer cell metabolism. FGFR3-TACC3 fusion-driven gliomas emerged as a defined subgroup with specific clinical, histological, and molecular features. Several FGFR inhibitors were tested in FGFR3-TACC3 fusion-positive gliomas and proved some efficacy, although inferior to the results seen in other FGFR3-TACC3 fusion-driven cancers. In this review, we summarize and discuss the state-of-the-art knowledge resulting from a 10-year research effort in the field, its clinical implications for glioma patients, the potential reasons for targeted therapy failures, and the perspective of emerging treatments.
Insights
FGFR3-TACC3 gene fusions drive specific glioblastomas and other cancers. This review covers 10 years of research, highlighting treatment challenges and future therapies for these fusion-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Recurrent fusions of the FGFR3 and TACC3 genes were discovered in 2012 as a key driver in a subset of human glioblastomas.
- FGFR3-TACC3 fusions are now recognized drivers in various solid tumors, influencing cancer cell metabolism.
Purpose of the Study:
- To review 10 years of research on FGFR3-TACC3 fusion-driven cancers, focusing on gliomas.
- To discuss clinical implications, reasons for targeted therapy limitations, and emerging treatment strategies.
Main Methods:
- Whole-transcriptome sequencing analysis identified FGFR3-TACC3 fusions.
- Review of preclinical and clinical studies investigating FGFR inhibitors and novel therapies.
Main Results:
- FGFR3-TACC3 fusion-positive gliomas represent a distinct subgroup with unique characteristics.
- FGFR inhibitors show some efficacy but are less effective in gliomas compared to other FGFR3-TACC3 fusion-driven cancers.
Conclusions:
- Understanding the molecular mechanisms and clinical features of FGFR3-TACC3 fusion-driven gliomas is crucial.
- Further research is needed to overcome therapeutic resistance and develop more effective treatments for these specific cancer types.
