SIRT6 haploinsufficiency results in H3K56 acetylation at the IGFBP2 locus, activating PI3K/AKT/mTOR, and facilitating melanoma resistance to MAPKi. IGF-1R inhibition restores sensitivity to MAPKi. Complete SIRT6 loss activates DNA damage response due to global chromosomal instability and increases MAPKi sensitivity. Here, SIRT6 is linked to melanoma.