Drug resistance in cancer: Principles of emergence and prevention
Drug resistance in cancer: Principles of emergence and prevention
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DOI：
10.1073/pnas.0501870102
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发表时间：
2005-07-05
影响因子：
11.1
通讯作者：
Wodarz, D
中科院分区：
文献类型：
--
作者：
Komarova, NL;Wodarz, D
尽管靶向治疗在治疗特定癌症方面取得了可喜的成果，但耐药性仍是一个问题。我们开发了一个数学框架，可用于研究用靶向小分子药物治疗的癌症中出现和预防耐药性的基本原理。我们考虑一个随机动力系统的基础上可测量的参数，如肿瘤细胞的周转率和耐药突变体的产生率。我们发现耐药性主要出现在治疗开始之前，对于高周转率的癌症，联合治疗不太可能产生优于单一药物治疗的优势。我们将数学框架应用于慢性粒细胞白血病。早期慢性粒细胞白血病是第一例用靶向药物伊马替尼（诺华，巴塞尔）成功治疗的病例。这种药物特异性抑制BCR-ABL癌基因，这是疾病进展所必需的。虽然耐药性阻止了疾病后期的成功治疗，但我们的计算表明，在模型假设范围内，具有不同特异性的三种靶向药物的组合可能会克服耐药性问题。
Although targeted therapy is yielding promising results in the treatment of specific cancers, drug resistance poses a problem. We develop a mathematical framework that can be used to study the principles underlying the emergence and prevention of resistance in cancers treated with targeted small-molecule drugs. We consider a stochastic dynamical system based on measurable parameters, such as the turnover rate of tumor cells and the rate at which resistant mutants are generated. We find that resistance arises mainly before the start of treatment and, for cancers with high turnover rates, combination therapy is less likely to yield an advantage over single-drug therapy. We apply the mathematical framework to chronic myeloid leukemia. Early-stage chronic myeloid leukemia was the first case to be treated successfully with a targeted drug, imatinib (Novartis, Basel). This drug specifically inhibits the BCR-ABL oncogene, which is required for progression. Although drug resistance prevents successful treatment at later stages of the disease, our calculations suggest that, within the model assumptions, a combination of three targeted drugs with different specificities might overcome the problem of resistance.