Tissue-specific oncogenic activity of K-RasA146T

KRAS is the most frequently mutated oncogene. The incidence of specific KRAS alleles varies between cancers from different sites, but it is unclear whether allelic selection results from biological selection for specific mutant K-Ras proteins. We used a cross-disciplinary approach to compare K-RasG12D, a common mutant form, and K-RasA146T, a mutant that occurs only in selected cancers. Biochemical and structural studies demonstrated that K-RasA146T exhibits a marked extension of switch 1 away from the protein body and nucleotide binding site, which activates K-Ras by promoting a high rate of intrinsic and GEF-induced nucleotide exchange. Using mice genetically engineered to express either allele, we found that K-RasG12D and K-RasA146T exhibit distinct tissue-specific effects on homeostasis that mirror mutational frequencies in human cancers. These tissue-specific phenotypes result from allele-specific signaling properties, demonstrating that context-dependent variations in signaling downstream of different K-Ras mutants drive the KRAS mutational pattern seen in cancer.