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

Fernanda I. Staquicini, Ming D. Qian, Ahmad Salameh, Andrey S. Dobroff, Julianna K. Edwards, Daniel F. Cimino, Benjamin J. Moeller, Patrick Kelly, Maria I. Nunez, Ximing Tang, Diane D. Liu, J. Jack Lee, Waun Ki Hong, Fortunato Ferrara, Andrew R.M. Bradbury, Roy R. Lobb, Martin J. Edelman, Richard L. Sidman, Ignacio I. Wistuba, Wadih ArapRenata Pasqualini

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish
Pages (from-to)7345-7359
Number of pages15
JournalJournal of Biological Chemistry
Volume290
Issue number12
DOIs
StatePublished - Mar 20 2015

Keywords

  • Animals
  • Antibodies, Monoclonal/immunology
  • Cell Cycle
  • Cell Line, Tumor
  • DNA Damage
  • DNA Repair
  • Humans
  • Lung Neoplasms/enzymology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Targeted Therapy
  • Radiation Tolerance
  • Rats
  • Rats, Nude
  • Receptor, EphA5/immunology

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