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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. In conclusion, 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:
 [1];  [2];  [2];  [1];  [2];  [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [1];  [3];  [4];  [4];  [5];  [2];  [1] more »;  [1] « less
  1. Univ. of Mexico School of Medicine, Albuquerque, NM (United States)
  2. Univ. of Texas M. D. Anderson Cancer Center, Houston, TX (United States)
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  4. Arrowhead Research Corp., Pasadena, CA (United States)
  5. Harvard Medical School, Boston, MA (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1225738
Report Number(s):
LA-UR-14-27894
Journal ID: ISSN 0021-9258
Grant/Contract Number:
AC52-06NA25396
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 290; Journal Issue: 12; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; cell cycle; DNA damage; DNA damage response; DNA repair; monoclonal antibody; receptor tyrosine kinase; ionizing radiation

Citation Formats

Staquicini, Fernanda I., Qian, Ming D., Salameh, Ahmad, Dobroff, Andrey S., Edwards, Julianna K., Cimino, Daniel F., Moeller, Benjamin J., Kelly, Patrick, Nunez, Maria I., Tang, Ximing, Liu, Diane D., Lee, J. Jack, Hong, Waun Ki, Ferrara, Fortunato, Bradbury, Andrew R. M., Lobb, Roy R., Edelman, Martin J., Sidman, Richard L., Wistuba, Ignacio I., Arap, Wadih, and Pasqualini, Renata. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer. United States: N. p., 2015. Web. doi:10.1074/jbc.M114.630525.
Staquicini, Fernanda I., Qian, Ming D., Salameh, Ahmad, Dobroff, Andrey S., Edwards, Julianna K., Cimino, Daniel F., Moeller, Benjamin J., Kelly, Patrick, Nunez, Maria I., Tang, Ximing, Liu, Diane D., Lee, J. Jack, Hong, Waun Ki, Ferrara, Fortunato, Bradbury, Andrew R. M., Lobb, Roy R., Edelman, Martin J., Sidman, Richard L., Wistuba, Ignacio I., Arap, Wadih, & Pasqualini, Renata. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer. United States. doi:10.1074/jbc.M114.630525.
Staquicini, Fernanda I., Qian, Ming D., Salameh, Ahmad, Dobroff, Andrey S., Edwards, Julianna K., Cimino, Daniel F., Moeller, Benjamin J., Kelly, Patrick, Nunez, Maria I., Tang, Ximing, Liu, Diane D., Lee, J. Jack, Hong, Waun Ki, Ferrara, Fortunato, Bradbury, Andrew R. M., Lobb, Roy R., Edelman, Martin J., Sidman, Richard L., Wistuba, Ignacio I., Arap, Wadih, and Pasqualini, Renata. Fri . "Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer". United States. doi:10.1074/jbc.M114.630525. https://www.osti.gov/servlets/purl/1225738.
@article{osti_1225738,
title = {Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer},
author = {Staquicini, Fernanda I. and Qian, Ming D. and Salameh, Ahmad and Dobroff, Andrey S. and Edwards, Julianna K. and Cimino, Daniel F. and Moeller, Benjamin J. and Kelly, Patrick and Nunez, Maria I. and Tang, Ximing and Liu, Diane D. and Lee, J. Jack and Hong, Waun Ki and Ferrara, Fortunato and Bradbury, Andrew R. M. and Lobb, Roy R. and Edelman, Martin J. and Sidman, Richard L. and Wistuba, Ignacio I. and Arap, Wadih and Pasqualini, Renata},
abstractNote = {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. In conclusion, 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.},
doi = {10.1074/jbc.M114.630525},
journal = {Journal of Biological Chemistry},
number = 12,
volume = 290,
place = {United States},
year = {Fri Mar 20 00:00:00 EDT 2015},
month = {Fri Mar 20 00:00:00 EDT 2015}
}

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Cited by: 9 works
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