title: Targeting Fibroblast Growth Factor Receptor 1 for Treatment of Soft-Tissue Sarcoma.
abstract: 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 ofFGFR1amplification 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:IncreasedFGFR1copy 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.FGFR1overexpression 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 identifyFGFR1as 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.
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Priya
authors.initials: P
authors.lastname: Chudasama
authors.affiliation: Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Renner
authors.affiliation: Institute of Pathology, Technische Universität München, Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Straub
authors.affiliation: Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany.
authors.forename: Sadaf S
authors.initials: SS
authors.lastname: Mughal
authors.affiliation: Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hutter
authors.affiliation: Clinical Cooperation Unit Applied Tumor Immunity, DKFZ and NCT Heidelberg, Heidelberg, Germany.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Kosaloglu
authors.affiliation: Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany.
authors.forename: Ron
authors.initials: R
authors.lastname: Schweßinger
authors.affiliation: Department of Internal Medicine I, Center for Integrated Oncology, Cologne University Hospital, Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheffler
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Alldinger
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Schimmack
authors.affiliation: Department of Radiology, Cologne University Hospital, Cologne, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Persigehl
authors.affiliation: Department of Nuclear Medicine, Cologne University Hospital, Cologne, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Kobe
authors.affiliation: Clinical Cooperation Unit Applied Tumor Immunity, DKFZ and NCT Heidelberg, Heidelberg, Germany.|Department of Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.|German Cancer Consortium, Heidelberg, Germany.|DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.affiliation: Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.|German Cancer Consortium, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Genomics and Proteomics Core Facility, DKFZ, Heidelberg, Germany.
authors.forename: Marie-Kristin
authors.initials: MK
authors.lastname: Beckhaus
authors.affiliation: German Cancer Consortium, Heidelberg, Germany.|Genomics and Proteomics Core Facility, DKFZ, Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wolf
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Heining
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gröschel
authors.affiliation: Department of Internal Medicine I, Center for Integrated Oncology, Cologne University Hospital, Cologne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany.|German Cancer Consortium, Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Institute of Pathology, Technische Universität München, Munich, Germany.|German Cancer Consortium, Munich, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.|German Cancer Consortium, Heidelberg, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium, Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
authors.affiliation: Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Gunhild
authors.initials: G
authors.lastname: Mechtersheimer
authors.affiliation: Institute of Pathology, Technische Universität München, Munich, Germany.|German Cancer Consortium, Munich, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Specht
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.|German Cancer Consortium, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D012333:RNA, Messenger; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: C572463:AZD4547; D001549:Benzamides; C115711:PD 173074; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1