title: Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer.
abstract: Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. Finally, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications.
authors.affiliation: From the University of New Mexico Cancer Center and the Divisions of Molecular Medicine and.
authors.forename: Fernanda I
authors.initials: FI
authors.lastname: Staquicini
authors.affiliation: the Departments of Genitourinary Medical Oncology.
authors.forename: Ming D
authors.initials: MD
authors.lastname: Qian
authors.affiliation: the Departments of Genitourinary Medical Oncology.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Salameh
authors.affiliation: From the University of New Mexico Cancer Center and the Divisions of Molecular Medicine and.
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Dobroff
authors.affiliation: the Departments of Genitourinary Medical Oncology.
authors.forename: Julianna K
authors.initials: JK
authors.lastname: Edwards
authors.affiliation: From the University of New Mexico Cancer Center and the Divisions of Molecular Medicine and.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Cimino
authors.affiliation: the Departments of Genitourinary Medical Oncology, Radiation Oncology.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Moeller
authors.affiliation: the Departments of Genitourinary Medical Oncology, Radiation Oncology.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kelly
authors.affiliation: Translational Molecular Pathology.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Nunez
authors.affiliation: Translational Molecular Pathology.
authors.forename: Ximing
authors.initials: X
authors.lastname: Tang
authors.affiliation: Biostatistics, and.
authors.forename: Diane D
authors.initials: DD
authors.lastname: Liu
authors.affiliation: Biostatistics, and.
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Thoracic/Head & Neck Medical Oncology, David H. Koch Center, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.affiliation: From the University of New Mexico Cancer Center and the Divisions of Molecular Medicine and.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ferrara
authors.affiliation: the Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545.
authors.forename: Andrew R M
authors.initials: AR
authors.lastname: Bradbury
authors.affiliation: Alvos Therapeutics, Arrowhead Research Corporation, Pasadena, California 91101.
authors.forename: Roy R
authors.initials: RR
authors.lastname: Lobb
authors.affiliation: Alvos Therapeutics, Arrowhead Research Corporation, Pasadena, California 91101.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Edelman
authors.affiliation: the Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.affiliation: Translational Molecular Pathology.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: From the University of New Mexico Cancer Center and Hematology/Medical Oncology, Department of Internal Medicine University of New Mexico School of Medicine, Albuquerque, New Mexico 87131-0001, warap@salud.unm.edu.
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.affiliation: From the University of New Mexico Cancer Center and the Divisions of Molecular Medicine and rpasqual@salud.unm.edu.
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D011836:Radiation Tolerance; D051381:Rats; D011923:Rats, Nude; D036123:Receptor, EphA5 / Q000276:immunology / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; C484173:EPHA5 protein, human; D036123:Receptor, EphA5
keywords: Cell Cycle; DNA Damage; DNA Damage Response; DNA Repair; Ionizing Radiation; Monoclonal Antibody; Receptor Tyrosine Kinase