This study reveals that MYC overexpression promotes resistance to CDK4/6 inhibitors (CDK4/6i) by inducing degradation of the tumor suppressor protein pRB1. MYC enhances the transcription of the E3 ubiquitin ligase KLHL42, which leads to the ubiquitination and degradation of pRB1. This mechanism reduces pRB1 levels, thereby impairing CDK4/6i efficacy. The researchers identified A80.2HCl, a compound that degrades MYC at nanomolar concentrations, which restores pRB1 levels and re-sensitizes MYC-high expressing cancer cells to CDK4/6i. When combined with CDK4/6i, A80.2HCl significantly reduces tumor growth in vivo. These findings highlight the role of MYC in CDK4/6i resistance and suggest that targeting MYC with compounds like A80.2HCl could enhance the therapeutic effectiveness of CDK4/6i in cancer treatment. The study also demonstrates that KLHL42, a transcriptional target of MYC, contributes to pRB1 degradation and CDK4/6i resistance. The results provide insights into the molecular mechanisms underlying MYC-induced resistance and offer a potential strategy for overcoming CDK4/6i resistance in cancers.This study reveals that MYC overexpression promotes resistance to CDK4/6 inhibitors (CDK4/6i) by inducing degradation of the tumor suppressor protein pRB1. MYC enhances the transcription of the E3 ubiquitin ligase KLHL42, which leads to the ubiquitination and degradation of pRB1. This mechanism reduces pRB1 levels, thereby impairing CDK4/6i efficacy. The researchers identified A80.2HCl, a compound that degrades MYC at nanomolar concentrations, which restores pRB1 levels and re-sensitizes MYC-high expressing cancer cells to CDK4/6i. When combined with CDK4/6i, A80.2HCl significantly reduces tumor growth in vivo. These findings highlight the role of MYC in CDK4/6i resistance and suggest that targeting MYC with compounds like A80.2HCl could enhance the therapeutic effectiveness of CDK4/6i in cancer treatment. The study also demonstrates that KLHL42, a transcriptional target of MYC, contributes to pRB1 degradation and CDK4/6i resistance. The results provide insights into the molecular mechanisms underlying MYC-induced resistance and offer a potential strategy for overcoming CDK4/6i resistance in cancers.