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.

中文翻译：

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克服对 BRAF 抑制剂的耐药性

人类黑色素瘤中最常见的突变之一是 B-raf 基因，使其蛋白质 BRAF 成为治疗的关键目标。然而，在接受 BRAF 抑制剂（BRAFi）治疗的患者中，虽然一开始反应非常好，但平均在 6 个月内会复发。为了克服这种对 BRAFi 的耐药性，已经探索了 BRAFi 与其他药物的各种组合，有些正在临床应用，例如 BRAF 和 MEK 抑制剂的组合。小鼠黑色素瘤的实验数据表明，在BRAFi持续治疗下，促癌MDSCs和趋化因子CCL2最初减少但最终增加到原始水平以上，而抗癌T细胞不断减少。在本文中，我们开发了一个数学模型来解释这些实验结果。