title: Somatic mutations lead to an oncogenic deletion of met in lung cancer.
abstract: Activating mutations in receptor tyrosine kinases play a critical role in oncogenesis. Despite evidence that Met kinase is deregulated in human cancer, the role of activating mutations in cancers other than renal papillary carcinoma has not been well defined. Here we report the identification of somatic intronic mutations of Met kinase that lead to an alternatively spliced transcript in lung cancer, which encodes a deletion of the juxtamembrane domain resulting in the loss of Cbl E3-ligase binding. The mutant receptor exhibits decreased ubiquitination and delayed down-regulation correlating with elevated, distinct Met expression in primary tumors harboring the deleted receptor. As a consequence, phospho-Met and downstream mitogen-activated protein kinase activation is sustained on ligand stimulation. Cells expressing the Met deletion reveal enhanced ligand-mediated proliferation and significant in vivo tumor growth. A hepatocyte growth factor competitive Met antagonist inhibits receptor activation and proliferation in tumor cells harboring the Met deletion, suggesting the important role played by ligand-dependent Met activation and the potential for anticancer therapy. These results support a critical role for Met in lung cancer and somatic mutation-driven splicing of an oncogene that leads to a different mechanism for tyrosine kinase activation through altered receptor down-regulation in human cancer.
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94114, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Kong-Beltran
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Jiping
authors.initials: J
authors.lastname: Zha
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhu
authors.forename: Kaumudi
authors.initials: K
authors.lastname: Bhawe
authors.forename: Nerissa
authors.initials: N
authors.lastname: Mendoza
authors.forename: Thomas
authors.initials: T
authors.lastname: Holcomb
authors.forename: Kanan
authors.initials: K
authors.lastname: Pujara
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Ling
authors.initials: L
authors.lastname: Fu
authors.forename: Christophe
authors.initials: C
authors.lastname: Severin
authors.forename: Linda
authors.initials: L
authors.lastname: Rangell
authors.forename: Ralph
authors.initials: R
authors.lastname: Schwall
authors.forename: Lukas
authors.initials: L
authors.lastname: Amler
authors.forename: Dineli
authors.initials: D
authors.lastname: Wickramasinghe
authors.forename: Robert
authors.initials: R
authors.lastname: Yauch
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D005091:Exons; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007438:Introns; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D025801:Ubiquitin; D050721:Proto-Oncogene Proteins c-cbl; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020928:Mitogen-Activated Protein Kinases