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Ref Type Journal Article
PMID (27535980)
Authors Chudasama P, Renner M, Straub M, Mughal SS, Hutter B, Kosaloglu Z, Schweßinger R, Scheffler M, Alldinger I, Schimmack S, Persigehl T, Kobe C, Jäger D, von Kalle C, Schirmacher P, Beckhaus MK, Wolf S, Heining C, Gröschel S, Wolf J, Brors B, Weichert W, Glimm H, Scholl C, Mechtersheimer G, Specht K, Fröhling S
Title Targeting Fibroblast Growth Factor Receptor 1 for Treatment of Soft-Tissue Sarcoma.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 23 4 2017 Feb 15 962-973 Clin Cancer Res
URL
Abstract Text Purpose: Altered FGFR1 signaling has emerged as a therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties of FGFR1 and its potential as a drug target in patients with STS.Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by FISH, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis.Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; cohort 1), 13 of 79 (16.5%; cohort 2), and 80 of 254 (31.5%; cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, cohort 2) and 39 of 254 (15.4%; cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway.Conclusions: These data identify FGFR1 as a driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to the FGFR1 expression and monitoring of MAPK-ERK1/2 signaling, as a therapeutic option in this challenging group of diseases. Clin Cancer Res; 23(4); 962-73. ©2016 AACR.

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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
FGFR1 over exp uterus leiomyosarcoma sensitive Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited survival of FGFR1 over expressing uterus leiomyosarcoma cells in culture (PMID: 27535980). 27535980
FGFR1 positive synovial sarcoma decreased response Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, synovial sarcoma cells with moderate Fgfr1 expression level demonstrated decreased response to AZD4547 in culture (PMID: 27535980). 27535980
FGFR1 positive synovial sarcoma decreased response PD173074 Preclinical - Cell culture Actionable In a preclinical study, synovial sarcoma cells with moderate Fgfr1 expression level demonstrated decreased response to PD173074 in culture (PMID: 27535980). 27535980
FGFR1 positive leiomyosarcoma decreased response PD173074 Preclinical - Cell culture Actionable In a preclinical study, leiomyosarcoma cells with moderate Fgfr1 expression level demonstrated decreased response to PD173074 in culture (PMID: 27535980). 27535980
FGFR1 amp synovial sarcoma sensitive PD173074 Preclinical - Cell culture Actionable In a preclinical study, PD173074 inhibited survival of FGFR1 amplified synovial sarcoma cells in culture (PMID: 27535980). 27535980
FGFR1 positive leiomyosarcoma decreased response Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, leiomyosarcoma cells with moderate Fgfr1 expression level demonstrated decreased response to AZD4547 in culture (PMID: 27535980). 27535980
FGFR1 amp synovial sarcoma sensitive Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited survival of FGFR1 amplified synovial sarcoma cells in culture (PMID: 27535980). 27535980
FGFR1 positive uterus leiomyosarcoma decreased response Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, uterine leiomyosarcoma cells with moderate Fgfr1 expression level demonstrated decreased response to AZD4547 in culture (PMID: 27535980). 27535980
FGFR1 positive leiomyosarcoma decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, leiomyosarcoma cells with moderate Fgfr1 expression level demonstrated decreased response to Truseltiq (infigratinib) in culture (PMID: 27535980). 27535980
FGFR1 positive uterus leiomyosarcoma decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, uterine leiomyosarcoma cells with moderate Fgfr1 expression level demonstrated decreased response to Truseltiq (infigratinib) in culture (PMID: 27535980). 27535980
FGFR1 over exp uterus leiomyosarcoma sensitive PD173074 Preclinical - Cell culture Actionable In a preclinical study, PD173074 inhibited survival of FGFR1 over expressing uterus leiomyosarcoma cells in culture (PMID: 27535980). 27535980
FGFR1 positive synovial sarcoma decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, synovial sarcoma cells with moderate Fgfr1 expression level demonstrated decreased response to Truseltiq (infigratinib) in culture (PMID: 27535980). 27535980
FGFR1 over exp uterus leiomyosarcoma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited survival of FGFR1-overexpressing uterus leiomyosarcoma cells in culture (PMID: 27535980). 27535980
FGFR1 amp synovial sarcoma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited survival of FGFR1-amplified synovial sarcoma cells in culture (PMID: 27535980). 27535980
FGFR1 positive uterus leiomyosarcoma decreased response PD173074 Preclinical - Cell culture Actionable In a preclinical study, uterine leiomyosarcoma cells with moderate Fgfr1 expression level demonstrated decreased response to PD173074 in culture (PMID: 27535980). 27535980