title: Identification of the receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor, as therapeutic targets in clear cell sarcoma.
abstract: Clear cell sarcoma (CCS), a childhood tumor of the tendons and aponeuroses, is uniformly fatal once it has metastasized because of its profound therapeutic resistance. CCS is characterized by production of a chimeric transcription factor, EWS-ATF1, which is formed as the result of a disease-specific chromosomal translocation. EWS-ATF1 activates the melanocyte transcription factor MITF, which in turn activates transcription of c-Met, an oncogenic receptor tyrosine kinase recently shown to be activated in CCS. Based on this connection, we hypothesized that c-Met inhibition may offer a strategy to treat CCS, as an indirect tactic to defeat a transforming pathway downstream of EWS-ATF1. Here, we show that primary CCS and CCS-derived cell lines express c-Met, which is activated in an autocrine fashion by its ligand hepatocyte growth factor (HGF)/scatter factor in some CCS cell lines. c-Met expression is critical for CCS invasion, chemotaxis, and survival. Blocking c-Met activity with a small-molecule inhibitor (SU11274) or a neutralizing antibody to its ligand HGF (AMG 102) significantly reduced CCS cell growth in culture. Similarly, AMG 102 significantly suppressed in vivo tumor growth in an autocrine xenograft model of CCS. Collectively, these findings suggest the HGF:c-Met signaling axis as a candidate therapeutic target to improve clinical management of CCS.
authors.affiliation: Department of Pediatric Oncology, Ludwig Center for Cancer Research, Dana-Farber Cancer Institute, Children's Hospital Boston, Boston, Massachusetts, USA. dfisher3@partners.org
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Davis
authors.forename: Andrew W
authors.initials: AW
authors.lastname: McFadden
authors.forename: Yixiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Burgess
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis; D010879:Piperazines / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D018227:Sarcoma, Clear Cell / Q000188:drug therapy* / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; C111598:EWS-ATF1 fusion protein, human; D007211:Indoles; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D013449:Sulfonamides; D014157:Transcription Factors; C524459:rilotumumab; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met