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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.

Author information

1
Mathematical Biosciences Institute & Department of Mathematics, The Ohio State University, Columbus, OH, USA.
2
Department of Mathematics, The University of British Columbia Okanagan, Kelowna, BC, Canada. nourridine@aims.ac.za.

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.

KEYWORDS:

BRAF inhibitor resistance; Checkpoint inhibitors; Metastatic melanoma cancer

PMID:
31933021
DOI:
10.1007/s11538-019-00691-0

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