The long-term objective of this research project is to understand the role of heterodimerization in extracellular domains (ECD) of epidermal growth factor receptors (EGFRs) in cancer and to investigate its inhibition by novel peptidomimetics to explore strategies to generate targeted therapeutics. The short-term goals are to understand the role of domain IV of human epidermal growth factor receptor 2 (HER2), target the hot spot of domain IV to inhibit the protein-protein interactions of EGFRs, and study the implications of this in lung cancer. Among the lung cancers, non-small-cell lung cancer (NSCLC) is the most common and is a leading cause of cancer deaths worldwide. The prognosis of patients with lung cancer is poor, with a survival rate around one year, making it one of the least understood cancer types. EGFR are highly expressed in a variety of human tumors, including NSCLC. Approximately 18-33% of NSCLC tumors show HER2 overexpression, suggesting the importance of HER2 in NSCLC. The protein HER2 is known to interact with other EGFRs and form dimers/heteromers. The blockade of protein-protein interactions of HER2 with other EGFRs ultimately leads to control of cell growth and, hence, has therapeutic value for lung cancer patients. A peptidomimetic molecule has been designed that specifically binds to HER2 protein and inhibits the dimerization process of EGFR proteins. This approach is novel because the small molecule designed disrupts not only EGFR-HER2 dimerization but also HER2-HER3 dimerization. The coexpression of EGFR and HER2 has been associated with a significantly shortened overall survival rate of lung cancer patients. Thus, targeting HER2 and inhibiting EGFR:HER2 and HER2:HER3 dimerization will have a significant impact on HER2- overexpressed lung cancer. The exact mechanism of how the peptidomimetic molecule binds to HER2 and alters the HER2-mediated signaling is not well understood. The stability of the designed molecules for in vivo administration has not been characterized. We therefore propose to characterize details of the mechanism of binding of this newly designed compound to HER2 protein and its resulting effect on heterodimerization, phosphorylation, and downstream-signaling for cell growth. The following objectives will be investigated. 1) To optimize the compound for in vivo stability. 2) To understand the molecular mechanism of protein-protein interactions of EGFRs, its inhibition by the compounds developed, and its effect on downstream signaling. 3) To evaluate the therapeutic efficacy of an optimized compound in vivo using a lung cancer model. We expect that the results from this project will verify the importance of inhibition of dimerization by a peptidomimetic that binds to the HER2 extracellular domain. Such inhibitors that target multiple pathways of EGFRs signaling will have an impact on the survival rate of lung cancer patients, which is low at present. The research project described also provides research opportunities for undergraduate students and helps to create biomedical educational activities on campus.