Acquired resistance of metastatic melanoma (MM) tumors to BRAF V600E inhibitors 
(BRAFi's) is commonplace in the clinic. Habitual relapse of patients contributes 
to <20% 5-year survival rates in MM. We previously identified serine synthesis 
as a critical detrminant of late-stage cancer cell resistance to BRAFi's. 
Pre-treatment with DNA damaging agent gemcitabine (a nucleoside analog) 
re-sensitized drug-resistant cancer cells to BRAFi's dabrafenib and vemurafenib. 
Importantly, the combination treatments were effective against BRAF wild type 
cancer cells potentially expanding the clinical reach of BRAFi's. In this study, 
we identify the antifolate methotrexate (MTX) as a sensitizer of acquired- and 
intrinsically-resistant MM cells to BRAFi's dabrafenib and encorafenib. We 
identify a novel, positive correlation between dabrafenib treatments and repair 
delay of MTX induced single-strand DNA (ssDNA) breaks. Cells arrest in G1 phase 
following simultaneous MTX + dabrafenib treatments and eventually die via 
apoptosis. Importantly, we identify RAS codon 12 activating mutations as 
prognostic markers for MTX + BRAFi treatment efficacy. We describe a method of 
killing drug-resistant MM cells that if translated has the potential to improve 
MM patient survival.