Continuous MEK and CDK4/6 inhibition is effective in pre-clinical models, nevertheless, some tumors acquire resistance that was associated with enhanced phospho S6. To characterize the mechanism mediating the upregulation of mTOR-S6 pathway in these tumors, we performed RNA sequencing and targeted panel sequencing on xenograft tumors that progressed on either MEK plus CDK4/6 inhibitors (ComboR) or control diet. Gene set variance analysis (GSVA) revealed distinct gene expression signatures between the two ComboR tumors indicating heterogeneity. However, one of the 44 shared pathways between ComboR1 and ComboR2 included upregulation of an AKT pathway gene signature. By targeted sequencing and RNA sequencing, we observed high copy number change of NRAS in ComboR1 and a third tumor sample isolated from a continuous MEK inhibitor-intermittent CDK4/6 inhibitor schedule. NRAS was confirmed to mediate increased mTOR-S6 pathway activation suggesting that while distinct mechanisms are employed by melanoma tumors to circumvent MEK plus CDK4/6 inhibition, those resistance pathways eventually converge upon phosphorylation of S6 protein. Overall design: DNA or RNA were obtained from progressing WM1366 melanoma xenograft tumors treated with either control diet or the combination of MEK plus CDK4/6 inhibitor diet.