It is also notable that NICD1- or RFC4-overexpressing NSCLC cells are insensitive to γ-secretase inhibitor treatment, and several γ-secretase inhibitors already tested in phase I/II clinical trials for various types of cancers, including in NSCLC patients with refractory metastatic or locally advanced diseases, failed due to adverse effects and suboptimal efficacies, largely attributable to the complexity of Notch inhibition and possibly alternative oncogenic signaling contributed by other pathways48. This evidence concerns the gene RFC4 and glycogen storage disease VI.