Chudasama, Priya, Renner, Marcus, Straub, Melanie, Mughal, Sadaf S., Hutter, Barbara ORCID: 0000-0002-9034-0329, Kosaloglu, Zeynep, Schwessinger, Ron ORCID: 0000-0001-7829-8503, Scheffler, Matthias ORCID: 0000-0002-9031-1368, Alldinger, Ingo, Schimmack, Simon, Persigehl, Thorsten, Kobe, Carsten, Jaeger, Dirk, von Kalle, Christof, Schirmacher, Peter, Beckhaus, Marie-Kristin, Wolf, Stephan, Heining, Christoph, Groeschel, Stefan, Wolf, Juergen, Brors, Benedikt ORCID: 0000-0001-5940-3101, Weichert, Wilko, Glimm, Hanno, Scholl, Claudia, Mechtersheimer, Gunhild, Specht, Katja and Froehling, Stefan (2017). Targeting Fibroblast Growth Factor Receptor 1 for Treatment of Soft-Tissue Sarcoma. Clin. Cancer Res., 23 (4). S. 962 - 974. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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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 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. (C)2016 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Chudasama, PriyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renner, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Straub, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mughal, Sadaf S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hutter, BarbaraUNSPECIFIEDorcid.org/0000-0002-9034-0329UNSPECIFIED
Kosaloglu, ZeynepUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwessinger, RonUNSPECIFIEDorcid.org/0000-0001-7829-8503UNSPECIFIED
Scheffler, MatthiasUNSPECIFIEDorcid.org/0000-0002-9031-1368UNSPECIFIED
Alldinger, IngoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schimmack, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kobe, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaeger, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Kalle, ChristofUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schirmacher, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beckhaus, Marie-KristinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heining, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Groeschel, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brors, BenediktUNSPECIFIEDorcid.org/0000-0001-5940-3101UNSPECIFIED
Weichert, WilkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glimm, HannoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scholl, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mechtersheimer, GunhildUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Specht, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Froehling, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-241558
DOI: 10.1158/1078-0432.CCR-16-0860
Journal or Publication Title: Clin. Cancer Res.
Volume: 23
Number: 4
Page Range: S. 962 - 974
Date: 2017
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3265
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TYROSINE KINASE; DEDIFFERENTIATED LIPOSARCOMA; SELECTIVE INHIBITOR; CANCER GENOMICS; MESSENGER-RNA; LUNG-CANCER; COPY NUMBER; CELL-LINES; PATHWAY; SENSITIVITYMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/24155

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