Our findings that (1) drug holiday induced phosphorylation of ERK1/2, which is presumably responsible for the enhancement of MCL-1 stability and reduction in the BIM stability; (2) drug holiday increased NOXA level possibly diminishing the MCL-1 availability, suggest that alterations in the functional interactions among the BCL-2 family members might influence the susceptibility of trametinib-resistant melanoma cells to S63845. This evidence concerns the gene BCL2 and melanoma.