A Novel Approach for Targeting the Epidermal Growth Factor Receptor (EGFR) in Lung Cancer

Lung cancer is responsible for 28 percent of all cancer deaths and is a particular concern in Kentucky. Traditional treatment regimens, such as chemotherapy and radiation , attack proliferating cells rather tumor-specific protein targets, resulting in harsh side effects and limited efficacy. The development of targeted therapeutics for lung cancer represents a milestone in lung cancer treatment. One of the primary targets in lung cancer is EGFR (the epidermal growth factor receptor) , a trans-membrane tyrosine kinase that drives cell proliferation. EGFR is inhibited clinically with small molecule inhibitors like erlotinib and gefitinib/lressa and antibody fragments like erbituxlcetuximab. These drugs are most effective when drug responsive patients are identified prior to treatment based on the gene expression pattems of their tumors. The optimal expression pattems of patients for EGFR inhibitor treatment are still unclear, and there is a gap in our knowledge of the proteins that regulate EGFR stability and activation in lung cancer cells. The advantage of EGFR inhibitors is that they have relatively few side effects due to the specificity of their targets in tumors. However, the disadvantage is that EGFR inhibitors have a relatively small effect on patient outcomes because tumors quickly develop resistance to them. In this proposal, we describe a new component of the pathway that regulates EGFR stability. PGRMC1 (progesterone receptor membrane component 1) activates the cholesterol synthetic pathway and PGRMC1 stabilizes EGFR in lung cancer cells. We have developed a novel ligand for PGRMC1 that effectively kills lung cancer cells, at least in part by inhibiting EGFR. The hypothesis of the proposal is that PGRMC1 will synergize with other treatments for lung cancer, and tumor PGRMC1 levels will correlate with EGFR levels in clinical tumor samples. We will test the hypothesis by determining the extent to which (1) the PGRMC1 ligand sensitizes lung cancer cells to chemotherapy and inhibitors of EGFR and VEGF in vitro and in vivo. and (2) PGRMC1 predicts EGFR levels and clinical progression in lung cancer patients. The findings will be significant because they will provide a new therapeutic option for lung cancer patients that have developed resistance to EGFR inhibitors, and they will characterize a subset of patients that will likely respond to the therapy.