Supplementary figure S1 describes the molecular mechanisms of resistance across vemurafenib-resistant cell line models. Supplementary figure S2 serves as a repeat of figure 3a describing development of in vivo model of resistance, and demonstrates the effect of vemurafenib withdrawl on the resistant tumors. Supplementary figure S3 describes the effect of vemurafenib treatment on MAPK pathway inhibition in A375-RV2 cells. Supplementary figure S4 shows that selective cyclin D1 knockdown or CDK4/6 inhibition induces apoptosis in A375-R1 and M14-R vemurafenib-resistant melanoma cells.