Receptor Tyrosine Kinase EphA5 Is a Functional Molecular Target in Human Lung Cancer

Background: EphA5 is a functional target in lung cancer, the most common cause of tumor-related death in mankind. Results: EphA5 regulates cell cycle checkpoints and DNA damage repair induced by ionizing radiation. Conclusion: EphA5 is a novel regulator of DNA damage repair with clinical implications. Significance: EphA5 may serve as a novel biomarker of radioresistance and a candidate target for therapeutic intervention in human lung cancer. 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 G(1)/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.