MYC amplification confers resistance to CDK4/6 inhibitors (CDK4/6i) in bladder, prostate, and breast cancer cells. Mechanistically, MYC binds to the promoter of the E3 ubiquitin ligase KLHL42, enhancing its transcription and leading to RB1 deficiency by inducing both phosphorylated and total pRB1 ubiquitination and degradation. A compound, A80.2HCl, degrades MYC at nanomolar concentrations, restoring pRB1 protein levels and re-establishing sensitivity to CDK4/6i in MYC-high expressing cancer cells. The combination of CDK4/6i and A80.2HCl results in marked regression of tumor growth in vivo. These findings reveal the molecular mechanisms underlying MYC-induced resistance to CDK4/6i and suggest the use of A80.2HCl to potentiate the therapeutic efficacy of CDK4/6i.MYC amplification confers resistance to CDK4/6 inhibitors (CDK4/6i) in bladder, prostate, and breast cancer cells. Mechanistically, MYC binds to the promoter of the E3 ubiquitin ligase KLHL42, enhancing its transcription and leading to RB1 deficiency by inducing both phosphorylated and total pRB1 ubiquitination and degradation. A compound, A80.2HCl, degrades MYC at nanomolar concentrations, restoring pRB1 protein levels and re-establishing sensitivity to CDK4/6i in MYC-high expressing cancer cells. The combination of CDK4/6i and A80.2HCl results in marked regression of tumor growth in vivo. These findings reveal the molecular mechanisms underlying MYC-induced resistance to CDK4/6i and suggest the use of A80.2HCl to potentiate the therapeutic efficacy of CDK4/6i.