Joshua Cook, Giorgio Melloni, Peter J. Park (lab), Kevin M. Haigis (lab)
Mutational activation of the KRAS oncogene promotes initiation and/or progression of cancer in a variety of tissues. Though the mutant variants seemingly exert similar biological outputs, the biochemical properties and downstream signaling of each is distinct and highly context-dependent. As such, the genetic interactions associated with KRAS mutants are likely to vary according to the specific allele and the tissue-of-origin of the cancer. To explore this concept, 13,492 samples were collated from four tumor types with the highest frequency of mutation in KRAS: colorectal adenocarcinoma, lung adenocarcinoma, multiple myeloma, and pancreatic adenocarcinoma. Each cancer had a distinct spectrum of KRAS activating mutations that could not be predicted by the prevalence of known mutagenic mechanisms. Moreover, each allele was associated with a distinct comutation network that was also tissue-specific. Analyzing genetic dependencies highlighted cellular functions and individual genes that were or were not required for tumors with specific KRAS alleles. Overall, this analysis demonstrates that the KRAS alleles have distinct genetic interactions likely linked to their biological differences that can be further investigated as therapeutic targets.
