Overall, treatment of BRAF-mutant and RAS/RAF WT CRC respectively with a triple (pevonedistat, vemurafenib, and cetuximab) or a double (pevonedistat and lapatinib) combination, leading to effective concomitant targeting of the NEDD8 and the EGFR pathways, led to substantial improvements with respect to single pathway blockade, where no current therapeutic options seem effective. Here, NEDD8 is linked to colorectal carcinoma.