To develop targeted treatment for NF2-mutant cancers, Cooper et al. demonstrated that MLN4924, an NEDD8-activating enzyme (NAE) inhibitor, suppresses CRL4DCAF1 (E3 ubiquitin ligase) and interferes with YAP activation in NF2-mutant cancers alone, and in combination with, the PI3K-mTOR inhibitor, GDC-0980 [125]. Here, NEDD8 is linked to cancer.