Taken together these results indicate AZD5991 acts on-target in melanoma to inhibit MCL1 and strongly synergises with ERK1/2 pathway inhibitors that drive BIM and BMF expression to promote BAK/BAX-dependent apoptosis; this arises through redistribution of BIM and BMF from MCL1 on to other pro-survival proteins and an increase in free BIM, which may directly activate BAX. Here, BAK1 is linked to melanoma.