Oncotarget

Research Papers:

Methotrexate sensitizes drug-resistant metastatic melanoma cells to BRAF V600E inhibitors dabrafenib and encorafenib

Kayleigh C. Ross, Kevin F. Chin, Daehwan Kim, Christopher D. Marion, Timothy J. Yen and Vikram Bhattacharjee _

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Oncotarget. 2018; 9:13324-13336. https://doi.org/10.18632/oncotarget.24341

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Abstract

Kayleigh C. Ross1, Kevin F. Chin1, Daehwan Kim1, Christopher D. Marion1, Timothy J. Yen2 and Vikram Bhattacharjee1

1Evol Science, Philadelphia, PA 19104, USA

2Fox Chase Cancer Center, Philadelphia, PA 19111, USA

Correspondence to:

Vikram Bhattacharjee, email: vikram@evolscience.com

Keywords: dabrafenib, encorafenib, methotrexate, metastatic melanoma, pancreatic cancer

Received: December 23, 2017     Accepted: January 23, 2018     Published: January 29, 2018

ABSTRACT

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.


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