PROJECT ABSTRACT Lung cancer is the leading cause of cancer related deaths worldwide and lung cancer in never smokers is still among the top fatal cancers. Approximately 25% of lung cancers are driven by mutationally activated KRAS. A major obstacle in treating lung cancer is resistance to current therapeutic treatments. Recently, the first inhibitor of KRASG12C, sotorasib, was approved by the FDA for a subset of patients with KRASG12C driven lung cancer but primary and acquired resistance is arising. Currently, the field lacks a comprehensive understanding of how KRASG12C driven lung cancer cells survive after treatment with targeted therapy and how to overcome this. It is known that cancer cells can upregulate autophagy signaling, a nutrient scavenger pathway, in response to cellular stresses such as targeted therapy. Previous work has highlighted the impact of genetic silencing of essential autophagy genes Atg5 and Atg7 in KRAS driven lung cancer. We seek to test the impact of pharmacological inhibition of KRASG12C and its downstream signaling effectors on autophagy signaling and lung tumorigenesis in KRASG12C driven lung cancer models. We hypothesize that KRASG12C driven lung cancer cells increase autophagic flux after treatment with KRASG12C inhibitors and co-treatment with selective autophagy inhibitors will lead to superior delayed tumor growth. About 30% of lung cancer patients with KRAS mutations also have a deletions or inactivating mutations in LKB1, a protein involved in regulation of nutrient sensing and autophagy. KRAS-mutant lung cancer patients with loss of LKB1 expression are characterized by an aggressive behavior and resistance to standard treatment. In other KRAS-driven cancers, the LKB1-AMPK-ULK1 signaling axis is the proposed mechanism as to how autophagic flux increases following KRAS pathway inhibition. Preliminary data suggests LKB1 is dispensable for increases in autophagy flux after KRASG12C inhibition in KRAS mutant lung cancer cells with loss of LKB1 expression. We seek to test if LKB1 is necessary for autophagy signaling in KRASG12C driven lung cancer and if the ULK1/2 kinases activates autophagy independently of LKB1. To test this, we will use a novel murine model of KRASG12C driven lung cancer (KrasG12C-LSL) and human cell line models. Results accumulated from the study will lead to further findings that in turn will improve the health of lung cancer patients, including expanding the average life span after diagnosis.