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Ross KC , Chin KF , Kim D , Marion CD , Yen TJ , Bhattacharjee V
Methotrexate sensitizes drug-resistant metastatic melanoma cells to BRAF V600E inhibitors dabrafenib and encorafenib
Oncotarget. 2018 Mar 2;9(17) :13324-13336
PMID: 29568360    PMCID: PMC5862581   
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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.
1949-2553 Ross, Kayleigh C Chin, Kevin F Kim, Daehwan Marion, Christopher D Yen, Timothy J Bhattacharjee, Vikram P30 CA006927/CA/NCI NIH HHS/United States R21 CA191956/CA/NCI NIH HHS/United States Journal Article United States Oncotarget. 2018 Jan 29;9(17):13324-13336. doi: 10.18632/oncotarget.24341. eCollection 2018 Mar 2.