title: Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer.
abstract: Lung cancer outcomes remain poor despite the identification of several potential therapeutic targets. The EPHB4 receptor tyrosine kinase (RTK) has recently emerged as an oncogenic factor in many cancers, including lung cancer. Mutations of EPHB4 in lung cancers have previously been identified, though their significance remains unknown. Here, we report the identification of novel EPHB4 mutations that lead to putative structural alterations as well as increased cellular proliferation and motility. We also conducted a bioinformatic analysis of these mutations to demonstrate that they are mutually exclusive from other common RTK variants in lung cancer, that they correspond to analogous sites of other RTKs' variations in cancers, and that they are predicted to be oncogenic based on biochemical, evolutionary, and domain-function constraints. Finally, we show that EPHB4 mutations can induce broad changes in the kinome signature of lung cancer cells. Taken together, these data illuminate the role of EPHB4 in lung cancer and further identify EPHB4 as a potentially important therapeutic target.
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Ferguson
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Carol Tan
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Rajani S
authors.initials: RS
authors.lastname: Kanteti
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Ren
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gayed
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois, United States of America.|Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Ferguson
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: A
authors.initials: A
authors.lastname: John Iafrate
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Parkash S
authors.initials: PS
authors.lastname: Gill
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.|Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019295:Computational Biology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D034741:RNA, Small Interfering; D036224:Receptor, EphB4