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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.
Journal Science (New York, N.Y.)
Vol 337
Issue 6099
Date 2012 Sep 7
URL
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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR1 TACC1 FGFR1 - TACC1 fusion gain of function FGFR1-TACC1 results from the fusion of FGFR1 and TACC1, demonstrating transforming ability in culture, tumor growth in xenografts, and increased errors in chromosomal segregation (PMID: 22837387).
FGFR3 TACC3 FGFR3 - TACC3 fusion gain of function FGFR3-TACC3 results from the fusion of FGFR3 and TACC3, demonstrating constitutive kinase activity, transforming activity in culture, and ability to drive tumor growth in xenografts (PMID: 25294908, PMID: 22837387, PMID: 35138907). FGFR3-TACC3 has been identified in lung adenocarcinoma and glioblastoma (PMID: 25294908, PMID: 22837387).
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
FGFR3 - TACC3 high grade glioma sensitive PD173074 Preclinical - Cell line xenograft Actionable In a preclinical study, PD173074 inhibited Fgfr3 kinase activity and growth in transformed astrocytes expressing the FGFR3-TACC3 fusion in culture and in cell line xenograft models (PMID: 22837387). 22837387
FGFR1 - TACC1 high grade glioma sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited Fgfr1 kinase activity and cell growth in transformed cells expressing the FGFR1-TACC1 fusion in culture (PMID: 22837387). 22837387
FGFR1 - TACC1 high grade glioma sensitive PD173074 Preclinical - Cell culture Actionable In a preclinical study, PD173074 inhibited Fgfr1 kinase activity and cell growth in transformed cells expressing the FGFR1-TACC1 fusion in culture (PMID: 22837387). 22837387
FGFR3 - TACC3 high grade glioma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited Fgfr3 kinase activity in transformed astrocytes expressing the FGFR3-TACC3 fusion in culture (PMID: 22837387). 22837387
FGFR3 - TACC3 high grade glioma sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited Fgfr3 kinase activity in transformed astrocytes expressing the FGFR3-TACC3 fusion in culture (PMID: 22837387). 22837387
FGFR1 - TACC1 high grade glioma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited Fgfr1 kinase activity and cell growth in transformed cells expressing the FGFR1-TACC1 fusion in culture (PMID: 22837387). 22837387