IGF-1R blocking by cyclolignan picropodophyllin (PPP) increased TRAIL-induced apoptosis of both TRAIL-sensitive and TRAIL-resistant melanoma cell lines (113); moreover, combined treatment with PPP and trametinib induced apoptosis of BRAF-inhibitor resistant cells, which was associated with trametinib-dependent reduction of pERK and pBAD, PPP-dependent decreased pAkt and synergistically reduced Mcl-1 (114). This evidence concerns the gene TNFSF10 and melanoma.