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J Biol Chem. 2015 Mar 20;290(12):7345-59. doi: 10.1074/jbc.M114.630525. Epub 2015 Jan 26.

Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer.

Author information

1
From the University of New Mexico Cancer Center and the Divisions of Molecular Medicine and.
2
the Departments of Genitourinary Medical Oncology.
3
the Departments of Genitourinary Medical Oncology, Radiation Oncology.
4
Translational Molecular Pathology.
5
Biostatistics, and.
6
Thoracic/Head & Neck Medical Oncology, David H. Koch Center, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
7
the Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545.
8
Alvos Therapeutics, Arrowhead Research Corporation, Pasadena, California 91101.
9
the Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
10
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.
11
From the University of New Mexico Cancer Center and the Divisions of Molecular Medicine and rpasqual@salud.unm.edu.

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.

KEYWORDS:

Cell Cycle; DNA Damage; DNA Damage Response; DNA Repair; Ionizing Radiation; Monoclonal Antibody; Receptor Tyrosine Kinase

PMID:
25623065
PMCID:
PMC4367244
DOI:
10.1074/jbc.M114.630525
[Indexed for MEDLINE]
Free PMC Article

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