Our current study demonstrates that RFC4, which is amplified in the genomes of nearly 50% enrolled NSCLC cases, including both LUAD and squamous carcinoma subtypes, directly binds NICD1 with a high affinity to competitively abrogate CDK8-induced phosphorylation and FBXW7-induced ubiquitination-dependent degradation of NICD1, providing a biologically and clinically valid explanation for the observed increased NICD1 stability in the nucleus. This evidence concerns the gene RFC4 and non-small cell lung carcinoma.