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Ref Type | Journal Article | ||||||||||||
PMID | (22837387) | ||||||||||||
Authors | Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, Liu EM, Reichel J, Porrati P, Pellegatta S, Qiu K, Gao Z, Ceccarelli M, Riccardi R, Brat DJ, Guha A, Aldape K, Golfinos JG, Zagzag D, Mikkelsen T, Finocchiaro G, Lasorella A, Rabadan R, Iavarone A | ||||||||||||
Title | Transforming fusions of FGFR and TACC genes in human glioblastoma. | ||||||||||||
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Abstract Text | The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy, and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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FGFR3 | K508M | missense | loss of function | FGFR3 K508M lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). K508M confers a loss of function to the Fgfr3 protein as demonstrated by induction of growth arrest in cell culture and inactivation of Stat1 in vitro (PMID: 19088846) and loss of kinase activity in the context of Fgfr3-Tacc3 (PMID: 22837387). |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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