CDK6 and cancer: However, despite potent degradation of CDK6, these CRBN-based PROTACs have some limitations including off-target effects related to Ikaros transcription factors as well as a possible resistance of cancer cells to CRBN-based PROTACs through genetic CRBN inactivation.38 In general, gene expression levels of an E3 ligase component might affect the activity of the recruiting PROTAC, and tissue specificity may be guided by addressing different E3 ligases.