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Bull Math Biol. 2020 Jan 14;82(1):8. doi: 10.1007/s11538-019-00691-0.

Overcoming Drug Resistance to BRAF Inhibitor.

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Mathematical Biosciences Institute & Department of Mathematics, The Ohio State University, Columbus, OH, USA.
Department of Mathematics, The University of British Columbia Okanagan, Kelowna, BC, Canada.


One of the most frequently found mutations in human melanomas is in the B-raf gene, making its protein BRAF a key target for therapy. However, in patients treated with BRAF inhibitor (BRAFi), although the response is very good at first, relapse occurs within 6 months, on the average. In order to overcome this drug resistance to BRAFi, various combinations of BRAFi with other drugs have been explored, and some are being applied clinically, such as a combination of BRAF and MEK inhibitors. Experimental data for melanoma in mice show that under continuous treatment with BRAFi, the pro-cancer MDSCs and chemokine CCL2 initially decrease but eventually increase to above their original level, while the anticancer T cells continuously decrease. In this paper, we develop a mathematical model that explains these experimental results. The model is used to explore the efficacy of combinations of BRAFi with anti-CCL2, anti-PD-1 and anti-CTLA-4, with the aim of eliminating or reducing drug resistance to BRAFi.


BRAF inhibitor resistance; Checkpoint inhibitors; Metastatic melanoma cancer


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