title: Activating MET kinase rearrangements in melanoma and Spitz tumours.
abstract: Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumours with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumours lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K) and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist.
authors.affiliation: 1] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Iwei
authors.initials: I
authors.lastname: Yeh
authors.affiliation: 1] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Botton
authors.affiliation: 1] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Talevich
authors.affiliation: 1] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: A Hunter
authors.initials: AH
authors.lastname: Shain
authors.affiliation: 1] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Alyssa J
authors.initials: AJ
authors.lastname: Sparatta
authors.affiliation: Département de Biopathologie, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: de la Fouchardiere
authors.affiliation: Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Thaddeus W
authors.initials: TW
authors.lastname: Mully
authors.affiliation: Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: North
authors.affiliation: 1] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Garrido
authors.affiliation: Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gagnon
authors.affiliation: Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Swapna S
authors.initials: SS
authors.lastname: Vemula
authors.affiliation: 1] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: McCalmont
authors.affiliation: 1] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: LeBoit
authors.affiliation: 1] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D018332:Nevus, Epithelioid and Spindle Cell / Q000235:genetics*; D050596:Oncogene Fusion; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*
chemical_list: C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met