Baseline expression of c-Myc defines the tissue specificity of oncogenic K-Ras.

is among the most frequently mutated oncogenes in cancer. Yet, mutations in are common only in tumors originating from a subset of tissues. It is critical to understand the molecular mechanisms underlying this oncogene tissue specificity. Utilizing genetically engineered mouse models carrying a conditional oncogenic allele of , we expressed activated K-Ras in adult tissues to investigate its specificity. We discovered that the ability of K-Ras to influence the fitness of cells in a given tissue is not determined by its canonical signaling through MAPK. Instead, low baseline expression of c-Myc renders tissues non-permissive to oncogenic K-Ras, a context that can be reversed in the liver by ectopically expressing c-Myc. This functions independently of the proliferative index of the tissue or the induction of cell cycle arrest or apoptosis. Our findings reveal the importance of the basal state of the tissue-inherent signaling network for determining oncogene specificity.