Lung cancer is the leading cause of death by cancer in Europe. Non-small cell lung cancer (NSCLC) represents about 80% of total lung cancers. KRAS is the most commonly mutated oncogene in NSCLC, found in over 20% of patients. Since KRAS mutations are directly responsible for NSCLC, KRAS represents a relevant target to prevent NSCLC development. Yet, efforts to develop therapeutic inhibitors have failed for over 20 years, what represents an unmet clinical need in NSCLC. Thus, it is critical to identify targets of oncogenic KRAS that could unveil novel therapeutic candidates.In preliminary studies, molecular screening of downstream effectors of activated KRAS led to identification of several microRNAs. MiR-181a and b (miR-181a/b) were among the top microRNAs up-regulated upon KRAS activation. Moreover, genetic deletion of the miR-181ab1 cluster significantly impaired lung tumor development in vivo. These preliminary findings suggest a prominent role for miR-181a/b in KRAS oncogenesis. Thus, this proposal aims to dissect the role of miR-181a/b in the context of mutant KRAS to identify downstream target genes required for KRAS oncogenesis.We propose the following objectives:1. To investigate the role of miR-181ab-1 cluster in vivo and the potential therapeutic value of miR-181a and b using a genetically-modified mouse model of Kras-driven NSCLC.2. To uncover the functional role of miR-181a/b in human KRAS-driven oncogenesis using NSCLC cell lines and primary lung epithelial cells.3. To identify miR-181a/b-regulated genes functionally critical for KRAS-dependent NSCLC.4. To characterize the clinical implication of miR-181a/b-regulated genes in human NSCLC: translating in vitro and in vivo findings to human patients.We believe that results from this proposal will expand our current knowledge of the signaling network regulated by mutant KRAS. We hope to apply these findings to develop innovative therapeutic strategies for NSCLC patients harboring KRAS mutations