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|Ref Type||Journal Article|
|Authors||Williams SV, Hurst CD, Knowles MA|
|Title||Oncogenic FGFR3 gene fusions in bladder cancer.|
|Journal||Human molecular genetics|
|Date||2013 Feb 15|
|Abstract Text||FGF receptor 3 (FGFR3) is activated by mutation or over-expression in many bladder cancers. Here, we identify an additional mechanism of activation via chromosomal re-arrangement to generate constitutively activated fusion genes. FGFR3-transforming acid coiled coil 3 (TACC3) fusions resulting from 4p16.3 re-arrangements and a t(4;7) that generates a FGFR3-BAI1-associated protein 2-like 1 (BAIAP2L1) fusion were identified in 4 of 43 bladder tumour cell lines and 2 of 32 selected tissue samples including the tumour from which one of the cell lines was derived. These are highly activated and transform NIH-3T3 cells. The FGFR3 component is identical in all cases and lacks the final exon that includes the phospholipase C gamma 1 (PLCγ1) binding site. Expression of the fusions in immortalized normal human urothelial cells (NHUC) induced activation of the mitogen-activated protein kinase pathway but not PLCγ1. A protein with loss of the terminal region alone was not as highly activated as the fusion proteins, indicating that the fusion partners are essential. The TACC3 fusions retain the TACC domain that mediates microtubule binding and the BAIAP2L1 fusion retains the IRSp53/MIM domain (IMD) that mediates actin binding and Rac interaction. As urothelial cell lines with FGFR3 fusions are extremely sensitive to FGFR-selective agents, the presence of a fusion gene may aid in selection of patients for FGFR-targeted therapy.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|FGFR3||NCBI||ACH|CD333|CEK2|HSFGFR3EX|JTK4||FGFR3, fibroblast growth factor receptor 3, is a receptor tyrosine kinase activated upon binding of the FGF ligand, which activates RAS-MAPK and PI3K-AKT pathways (PMID: 22508544). Altered function of FGFR3 in cancer may lead to increased cell proliferation and decreased apoptosis (PMID: 22508544) and mutations and fusions are commonly observed in bladder cancer (PMID: 30975452, PMID: 23175443), while FGFR3 overexpression only in bladder cancer may have different treatment implications (PMID: 32682615).||Oncogene|
|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|
|FGFR3 BAIAP2L1||FGFR3 - BAIAP2L1||fusion||gain of function||FGFR3-BAIAP2L1 results from the fusion of FGFR3 and BAIAP2L1, demonstrating constitutive activation of downstream signaling and transformation of cells in culture (PMID: 23175443). FGFR3-BAIAP2L1 has been identified in bladder cancer (PMID: 23175443).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FGFR3 - TACC3||urinary bladder cancer||sensitive||AZ8010||Preclinical||Actionable||In a preclinical study, AZ12908010 (AZ8010) induced cell cycle arrest and inhibited proliferation of urothelial cancer cell lines that have been demonstrated to harbor FGFR3-TACC3 in culture (PMID: 22869148, PMID: 23175443).||22869148 23175443|
|FGFR3 - TACC3||urinary bladder cancer||sensitive||LY2874455||Preclinical||Actionable||In a preclinical study, LY2874455 induced tumor regression in bladder cancer xenograft models that have been demonstrated to harbor an FGFR3-TACC3 fusion (PMID: 21900693, PMID: 23175443).||21900693 23175443|
|FGFR3 - TACC3||urinary bladder cancer||predicted - sensitive||S-49076||Preclinical||Actionable||In a preclinical study, S-49076 inhibited autophosphorylation of FGFR3 and downstream signaling in bladder cancer cells that have been demonstrated to harbor FGFR3-TACC3 in culture (PMID: 23804704, PMID: 23175443).||23175443 23804704|
|FGFR3 - TACC3||urinary bladder cancer||sensitive||SU5402||Preclinical||Actionable||In a preclinical study, SU5402 induced cell-cycle arrest and inhibited proliferation of bladder cancer cells that have been demonstrated to harbor FGFR3-TACC3 in culture (PMID: 21119661, PMID: 23175443).||21119661 23175443|
|FGFR3 - TACC3||urinary bladder cancer||sensitive||Dovitinib||Preclinical||Actionable||In a preclinical study, Dovitinib (TKI258) inhibited growth of bladder cancer cell lines that have been demonstrated to harbor FGFR3-TACC3 in culture (PMID: 24325461, PMID: 23175443).||23175443 24325461|
|FGFR3 - TACC3||urinary bladder cancer||sensitive||FIIN-1||Preclinical||Actionable||In a preclinical study, FIIN-1 inhibited growth of the RT4 bladder cancer cell line, which has been demonstrated to harbor an FGFR3-TACC3 fusion, in culture (PMID: 20338520, PMID: 23175443).||23175443 20338520|