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Ref Type Journal Article
PMID (25589496)
Authors Nakanishi Y, Akiyama N, Tsukaguchi T, Fujii T, Satoh Y, Ishii N, Aoki M
Title Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase FGFR3-BAIAP2L1.
Journal Molecular cancer therapeutics
Vol 14
Issue 3
Date 2015 Mar
URL
Abstract Text Recent cancer genome profiling studies have identified many novel genetic alterations, including rearrangements of genes encoding FGFR family members. However, most fusion genes are not functionally characterized, and their potentials in targeted therapy are unclear. We investigated a recently discovered gene fusion between FGFR3 and BAI1-associated protein 2-like 1 (BAIAP2L1). We identified 4 patients with bladder cancer and 2 patients with lung cancer harboring the FGFR3-BAIAP2L1 fusion through PCR and FISH assay screens. To investigate the oncogenic potential of the fusion gene, we established an FGFR3-BAIAP2L1 transfectant with Rat-2 fibroblast cells (Rat-2_F3-B). The FGFR3-BAIAP2L1 fusion had transforming activity in Rat2 cells, and Rat-2_F3-B cells were highly tumorigenic in mice. Rat-2_F3-B cells showed in vitro and in vivo sensitivity in the selective FGFR inhibitor CH5183284/Debio 1347, indicating that FGFR3 kinase activity is critical for tumorigenesis. Gene signature analysis revealed that FGFR3-BAIAP2L1 activates growth signals, such as the MAPK pathway, and inhibits tumor-suppressive signals, such as the p53, RB1, and CDKN2A pathways. We also established Rat-2_F3-B-ΔBAR cells expressing an FGFR3-BAIAP2L1 variant lacking the Bin-Amphiphysin-Rvs (BAR) dimerization domain of BAIAP2L1, which exhibited decreased tumorigenic activity, FGFR3 phosphorylation, and F3-B-ΔBAR dimerization, compared with Rat-2_F3-B cells. Collectively, these data suggest that constitutive dimerization through the BAR domain promotes constitutive FGFR3 kinase activation and is essential for its potent oncogenic activity.

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 - BAIAP2L1 urinary bladder cancer sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Infigratinib (BGJ398) inhibited proliferation of a bladder cancer cell line harboring FGFR3-BAIAP2L1 in culture (PMID: 25589496). 25589496
FGFR3 - BAIAP2L1 urinary bladder cancer sensitive PD173074 Preclinical - Cell culture Actionable In a preclinical study, PD173074 inhibited proliferation of a bladder cancer cell line harboring FGFR3-BAIAP2L1 in culture (PMID: 25589496). 25589496
FGFR3 - BAIAP2L1 urinary bladder cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited proliferation of a bladder cancer cell line harboring FGFR3-BAIAP2L1 in culture (PMID: 25589496). 25589496
FGFR3 - BAIAP2L1 urinary bladder cancer sensitive Dovitinib Preclinical - Cell culture Actionable In a preclinical study, Dovitinib (TKI258) inhibited proliferation of a bladder cancer cell line harboring FGFR3-BAIAP2L1 in culture (PMID: 25589496). 25589496
FGFR3 - BAIAP2L1 urinary bladder cancer sensitive Cediranib Preclinical - Cell culture Actionable In a preclinical study, Cediranib (AZD-2171) inhibited proliferation of a bladder cancer cell line harboring FGFR3-BAIAP2L1 in culture (PMID: 25589496). 25589496
FGFR3 - BAIAP2L1 urinary bladder cancer sensitive Debio 1347 Preclinical - Cell line xenograft Actionable In a preclinical study, Debio 1347 decreased phosphorylation of ERK and FRS and inhibited proliferation of a bladder cancer cell line harboring FGFR3-BAIAP2L1 in culture, and inhibited tumor growth in bladder cancer cell line xenograft models with FGFR3-BAIAP2L1 (PMID: 25589496) 25589496