EphA2 receptor tyrosine kinase is frequently overexpressed in various human cancers, leading to the suggestion that it may be an oncoprotein. Surprisingly, recent studies from the applicant’s laboratory show that EphA2 is a novel tumor suppressor gene in mammalian lung, and is an attractive target for lung cancer therapy. Multiple lines of evidence support this notion: 1) EphA2 homozygous knockout mice but not their wild type littermates displayed markedly increased susceptibility to chemically induced lung carcinogenesis. 2) Intriguingly, unlike conventional tumor suppressor genes that are lost or mutated in tumors, EphA2 was consistently upregulated in tumors arising in wild type mice. The overexpression is robust and occurs very early, even in preneoplastic lesions. 3) However, the overexpressed EphA2 is poorly activated in mouse tumors in vivo and human NSCLC cells in vitro, suggesting that tumor suppressor activities of EphA2 have been functionally silenced during tumorigenesis. 4) In human NSCLC cells in vitro, the latent tumor suppressor function of EphA2 can be reawakened by stimulation with ephrin-A1, a ligand for EphA2, and caused suppression of ERK1/2 and Akt kinase activities and inhibition of cell migration and proliferation. Forced expression of EphA2 on lung cancer cells sensitized cells to growth inhibition by rapamycin, and cotreatment with ephrin-A1 had cooperative inhibitory effects. 5) More importantly, we have demonstrated that systemic administration of ephrin-A1-Fc led to selective homing of the ligand to tumors that overexpress the dormant EphA2, and activated it.

The overarching goal of this proposal is to uncover the molecular mechanisms of the tumor suppressor function of EphA2 kinase in mammalian lung, and to test if the intrinsic tumor suppressor activities of EphA2 kinase can be harnessed for lung cancer therapy. Aim 1 will test the effects of EphA2 deletion on lung oncogenesis induced by mutant K-Ras and p53. In Aim 2, ephrin-A1 will be systemically administered to test its therapeutic efficacy against lung tumors by itself or in combination with other agents including rapamycin and conventional cytotoxic drugs. The proposed studies will lead to the characterization of a novel lung tumor suppressor gene, and an innovative paradigm of exploiting innate tumor suppressor function of EphA2 kinase for therapeutic intervention of lung cancer.