Moreover, RFC4 tightly binds NICD1 to competitively abrogate CDK8/FBXW7-mediated phosphorylation and polyubiquitination to stabilize NICD1 proteins and overactivates Notch signaling in a positive feedback manner, conferring NSCLC cells both metastasis and stemness properties and resistance to γ-secretase inhibitor treatment, suggesting the therapeutic, diagnostic, and prognostic potential of the positive feedback loop consisting of high RFC4 and NICD1 levels. Here, RFC4 is linked to non-small cell lung carcinoma.