To reinforce the role of SMAD3 in BRAFi resistance, we showed that gain‐of‐function of SMAD3 significantly increases the BRAFi resistance of melanoma cells when compared to different control cells (parental 501Mel cells and the CRISPR‐engineered cells: 501Mel cells expressing dCas9 and HSF1‐p65‐MS2 (named here 501Mel 2+) and the 501Mel 2+ cells expressing a control guide (named 3+ backbone; Fig 5D). Here, SMAD3 is linked to melanoma.