In summary, we evaluated a novel combination of MEK and CDK4/6 inhibitors in KRAS mutant CRCs and found synergistic inhibition of cell growth in vitro, with contributions of decreased proliferation, increased apoptosis, and increased senescence; and we subsequently found the combination of MEK and CDK4/6 inhibitors caused tumor regression in vivo in cell line and patient-derived xenografts. This evidence concerns the gene KRAS and neoplasm.