title: Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4.
abstract: Tyrosine phosphorylation is important in signaling pathways underlying tumorigenesis. We performed a mutational analysis of the protein tyrosine kinase (PTK) gene family in cutaneous metastatic melanoma. We identified 30 somatic mutations affecting the kinase domains of 19 PTKs and subsequently evaluated the entire coding regions of the genes encoding these 19 PTKs for somatic mutations in 79 melanoma samples. We found ERBB4 mutations in 19% of individuals with melanoma and found mutations in two other kinases (FLT1 and PTK2B) in 10% of individuals with melanomas. We examined seven missense mutations in the most commonly altered PTK gene, ERBB4, and found that they resulted in increased kinase activity and transformation ability. Melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA-mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib. These studies could lead to personalized therapeutics specifically targeting the kinases that are mutationally altered in individual melanomas.
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Prickett
authors.forename: Neena S
authors.initials: NS
authors.lastname: Agrawal
authors.forename: Xiaomu
authors.initials: X
authors.lastname: Wei
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Yates
authors.forename: Jimmy C
authors.initials: JC
authors.lastname: Lin
authors.forename: John R
authors.initials: JR
authors.lastname: Wunderlich
authors.forename: Julia C
authors.initials: JC
authors.lastname: Cronin
authors.forename: Pedro
authors.initials: P
authors.lastname: Cruz
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Yardena
authors.initials: Y
authors.lastname: Samuels
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D000077341:Lapatinib; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000032:analysis* / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D066247:Receptor, ErbB-4; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077341:Lapatinib; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D011505:Protein-Tyrosine Kinases; D066247:Receptor, ErbB-4