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Overcoming Drug Resistance to BRAF Inhibitor

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Abstract

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.

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  1. Mathematical Biosciences Institute & Department of Mathematics, The Ohio State University, Columbus, OH, USA

    Avner Friedman

  2. Department of Mathematics, The University of British Columbia Okanagan, Kelowna, BC, Canada

    Nourridine Siewe

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Friedman, A., Siewe, N. Overcoming Drug Resistance to BRAF Inhibitor. Bull Math Biol 82, 8 (2020). https://doi.org/10.1007/s11538-019-00691-0

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