Lung cancer is the leading cause of cancer death in the US and worldwide, and non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. A subset of these cancers has a “driver” gene mutation the epidermal growth factor receptor (EGFR) for which targeted agents are highly effective in causing tumors to shrink. However, it never cures patients and the tumor always grows back. This proposal focuses on why the cancer is not completely killed even though all of the tumor cells have this mutation, and how to overcome this problem and kill the cancer more thoroughly. Our published and preliminary data have demonstrated that targeted therapy rapidly induces drug persistent cancer stem cells (DPCs) within days of starting therapy, and these DPCs don’t die with the drug. We show that this therapy specifically activates other genes called Notch3 and β-catenin that are essential for this effect. We show in animal experiments that targeting both EGFR and β-catenin result in reduced numbers of DPCs, and improved depth and duration of response and overall survival. This is a completely different approach than trying to target drug “resistance” pathways that develop months after initiation of therapy due to the “persistence” of tumor in the early days of therapy. Our goal is to eliminate tumor persistence so that it doesn’t have the chance to develop resistance, resulting in the cure of these patients. In this application, we propose to study how this persistence happens and attempt to move toward curing these patients by targeting β-catenin in combination with EGFR in a pilot human clinical trial. Successful completion of the proposed research will increase our understanding of why tumor cells are not eradicated with EGFR targeted therapy and test a novel drug combination that we hope will improve the survival of these patients.