TERT promoter mutation determines apoptotic and therapeutic responses of BRAF -mutant cancers to BRAF and MEK inhibitors: Achilles Heel

Significance The use of BRAF V600E-selective inhibitor dabrafenib and MEK inhibitor trametinib is a standard first-line treatment for human cancers harboringBRAF V600E. However, drug resistance/tumor recurrence is common with this treatment and the outcomes are unpredictable. We demonstrate here that dabrafenib and trametinib robustly induce cell apoptosis and hence abolishment of growth/regrowth of cancers harboring bothBRAF V600E andTERT promoter mutations with little effect in cells/tumors harboring onlyBRAF V600E. Thus,TERT promoter mutation, by governing the apoptotic and hence therapeutic sensitivities of BRAF-mutant cancer cells to BRAF/MEK inhibitors, may potentially be useful in helping patient selection for the inhibitor treatment and predicting therapeutic outcomes.