Using a focused CRISPR/Cas9 screen, we identify candidate TSGs whose upregulation is most likely involved in the phenotypic response to UHRF1 loss in cells expressing oncogenic KRAS. In GEMM and xenograft models of KRAS-driven lung cancer, homozygous UHRF1 loss significantly decreases tumor growth and extends survival. The gene discussed is UHRF1; the disease is neoplasm.