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Ref Type Journal Article
PMID (23558953)
Authors Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, Lonigro RJ, Vats P, Wang R, Lin SF, Cheng AJ, Kunju LP, Siddiqui J, Tomlins SA, Wyngaard P, Sadis S, Roychowdhury S, Hussain MH, Feng FY, Zalupski MM, Talpaz M, Pienta KJ, Rhodes DR, Robinson DR, Chinnaiyan AM
Title Identification of targetable FGFR gene fusions in diverse cancers.
Journal Cancer discovery
Vol 3
Issue 6
Date 2013 Jun
URL
Abstract Text Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2, including patients with cholangiocarcinoma, breast cancer, and prostate cancer. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins induced cell proliferation. Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Because of the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts, which incorporate transcriptome analysis for gene fusions, are poised to identify rare, targetable FGFR fusions across diverse cancer types.

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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
FGFR2 AFF3 FGFR2 - AFF3 fusion gain of function FGFR2-AFF3 results from the fusion of FGFR2 and AFF3 (PMID: 23558953), leading to activation of Fgfr downstream signaling and transformation in culture (PMID: 28416604). FGFR2-AFF3 has been identified in breast cancer (PMID: 23558953).
FGFR2 BICC1 FGFR2 - BICC1 fusion gain of function FGFR2-BICC1 results from the fusion of FGFR2 and BICC1, resulting in the ability to induce oligomerization, Fgfr kinase activity, Mapk signaling and transformation of cells in culture and in animal models (PMID: 23558953, PMID: 24122810, PMID: 28416604). FGFR2-BICC1 has been identified in intrahepatic cholangiocarcinoma (PMID: 25608663, PMID: 31899106).
FGFR2 CASP7 FGFR2 - CASP7 fusion gain of function FGFR2-CASP7 results from the fusion of FGFR2 and CASP7 (PMID: 23558953), leading to activation of Fgfr downstream signaling and transformation in culture (PMID: 28416604). FGFR2-CASP7 has been identified in breast cancer (PMID: 23558953).
FGFR2 CCAR2 FGFR2 - CCAR2 fusion unknown FGFR2-CCAR2 (also referred to as FGFR2-KIAA1967) results from the fusion of FGFR2 and CCAR2 (PMID: 23558953). FGFR2-CCAR2 has been identified in lung cancer (PMID: 27245147, PMID: 23558953), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Dec 2022).
FGFR2 CCDC6 FGFR2 - CCDC6 fusion gain of function FGFR2-CCDC6 results from the fusion of FGFR2 and CCDC6, resulting in the ability to induce oligomerization, activate Fgfr kinase activity, and induce cell proliferation (PMID: 23558953), and is transforming in culture (PMID: 28416604). FGFR2-CCDC6 has been identified in cholangiocarcinoma (PMID: 27216979).
FGFR2 CIT FGFR2 - CIT fusion unknown FGFR2-CIT results from the fusion of FGFR2 and CIT (PMID: 23558953). FGFR2-CIT has been identified in lung adenocarcinoma (PMID: 23558953) and adrenocortical carcinoma (PMID: 34410225), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Nov 2022).
FGFR2 OFD1 FGFR2 - OFD1 fusion gain of function FGFR2-OFD1 results from the fusion of FGFR2 and OFD1 (PMID: 23558953), leading to activation of Fgfr downstream signaling and transformation in culture (PMID: 28416604). FGFR2-OFD1 has been identified in thyroid carcinoma (PMID: 23558953).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 - BAIAP2L1 urinary bladder cancer sensitive Pazopanib Preclinical - Cell culture Actionable In a preclinical study, bladder cancer cells harboring FGFR3-BAIAP2L1 demonstrated sensitivity to Votrient (pazopanib) in culture (PMID: 23558953). 23558953
FGFR3 - TACC3 urinary bladder cancer sensitive PD173074 Preclinical - Cell line xenograft Actionable In a preclinical study, PD173074 inhibited tumor growth in cell line xenograft models of bladder cancer harboring FGFR3-TACC3 (PMID: 23558953). 23558953
FGFR3 S249C urinary bladder cancer resistant PD173074 Preclinical - Cell culture Actionable In a preclinical study, bladder cancer cells harboring FGFR3 S249C were resistant to PD173074 in culture (PMID: 23558953). 23558953
FGFR3 K652E urinary bladder cancer resistant PD173074 Preclinical - Cell line xenograft Actionable In a preclinical study, bladder cancer cells harboring FGFR3 K652E were resistant to PD173074 in culture and in cell line xenograft models (PMID: 23558953). 23558953
FGFR3 - BAIAP2L1 urinary bladder cancer sensitive PD173074 Preclinical - Cell line xenograft Actionable In a preclinical study, PD173074 inhibited growth of bladder cancer cells harboring FGFR3-BAIAP2L1 in culture, and inhibited tumor growth and ERK phosphorylation in cell line xenograft models (PMID: 23558953). 23558953
FGFR3 - TACC3 urinary bladder cancer sensitive Pazopanib Preclinical Actionable In a preclinical study, bladder cancer cells harboring FGFR3-TACC3 demonstrated sensitivity to Votrient (pazopanib) in culture (PMID: 23558953). 23558953