In CM, CDK4/6 inhibitor monotherapy is limited by upregulation of the MDM2-p53 and PRMT5-MDM4-p53 signaling axes (AbuHammad et al., 2019; Vilgelm et al., 2019), while resistance to combined CDK4/6i plus MEKi in NRAS-mutant melanoma is driven by genetic alterations in RTKs, RAF, RAS, and the PI3K/AKT signaling pathway (Hayes et al., 2019; Romano et al., 2018; Teh et al., 2018). This evidence concerns the gene TP53 and melanoma.