As inhibition of NEDD8-activating E1 enzyme (NAE1) blocks Cullin NEDDylation thereby rendering CRLs inactive (Fig. 1a), it was surprising that MLN4924 (TAK4924/Pevonedistat), a selective small-molecule inhibitor of the NAE1 [22], significantly enhanced rather than inhibited TRAIL-induced apoptosis in HCT116 colorectal cancer (CRC) (Fig. 1b and Supplementary Fig. 1a), A549 non-small cell lung cancer (NSCLC) and HT29 CRC (Supplementary Fig. 1b) cell lines. Here, CACUL1 is linked to colorectal cancer.