Kras mutant genetically engineered mouse models of human cancers are genomically heterogeneous

Significance RAS mutant cancers represent a large unmet clinical need. Kras mutant genetically engineered mouse models (GEMMs) of cancer recapitulate disease characteristics and are relied upon preclinically to validate targets and test therapies. Our integrative analysis of GEMM tumors revealed significantly evolved genetic heterogeneity, a common feature of human tumors that undermines therapeutic responses. Moreover, interspecies comparative analyses showed the extent of gene-level fidelity between altered oncogenes and tumor suppressors. The genomic diversity represents an unrecognized opportunity to identify therapeutically susceptible genomic subsets preclinically. Moreover, this more-thorough understanding of the unappreciated complexity in these model systems ultimately allows for better interpretation and translatability of preclinical GEMM data for the benefit of cancer patients.