ABSTRACT Individualized therapeutics for K-RAS mutant lung adenocarcinoma are nonexistent. Recently, we have described a unique interaction between activated K-Ras and the Type II cell that explains the unique ability of the Type II cell to proliferate in response to K-Ras activation. The absence of the transcription factor Sox2 allows Notch to be upregulated when K-Ras is activated. In addition, K-Ras is able to induce a transcriptional program that dedifferentiates distal lung epithelial cells into distal progenitors that are proliferative and multipotent during development. These distal stem cells express Sox9 as well as Ezh2. In this proposal, we will examine the effects of proximalizing Type II cells with Sox2 activation and Notch inhibition and Ezh2 inhibition on tumor initiation in Aim 1. This will involve inducible mouse transgenic alleles and human cell lines and human cells and tumors. We will also test the efficacy of a novel Sox2- mimetic compound, RepSox, for anti-tumor activity in K-Ras activated distal epithelial cells. In Aim 2, we will test the hypothesis that proximalization of the Type II cells suppresses progression of established K- Ras mutant adenocarcinomas. Finally, in Aim 3, we will assess the tumor suppression of Sox2 activation and Notch inhibition in more genetically complex tumors (K-Ras mutant, p53 knockout). We hypothesize that proximalization therapy will be tumor suppressive and potentially also chemosensitizing. Successful completion of these aims could help tens of thousands of patients per year. 1