The current clinical application of combination chemotherapy is guided by a historically successful set of practices that were developed by basic and clinical researchers 50-60 years ago. Thus, in order to understand how emerging approaches to drug development might aid the creation of new therapeutic combinations, it is critical to understand the defining principles underlying classic combination therapy and the original experimental rationales behind them. One such principle is that the use of combination therapies with independent mechanisms of action can minimize the evolution of drug resistance. Another is that in order to kill sufficient cancer cells to cure a patient, multiple drugs must be delivered at their maximum tolerated dose - a condition that allows for enhanced cancer cell killing with manageable toxicity. In light of these models, we aim to explore recent genomic evidence underlying the mechanisms of resistance to the combination regimens constructed on these principles. Interestingly, we find that emerging genomic evidence contradicts some of the rationales of early practitioners in developing commonly used drug regimens. However, we also find that the addition of recent targeted therapies has yet to change the current principles underlying the construction of anti-cancer combinatorial regimens, nor have they made substantial inroads into the treatment of most cancers. We suggest that emerging systems/network biology approaches have an immense opportunity to impact the rational development of successful drug regimens. Specifically, by examining drug combinations in multivariate ways, next generation combination therapies can be constructed with a clear understanding of how mechanisms of resistance to multi-drug regimens differ from single agent resistance.

中文翻译：

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了解对联合化疗的耐药性。

目前联合化疗的临床应用是由基础和临床研究人员在 50-60 年前开发的一系列历史上成功的实践指导的。因此，为了了解新兴的药物开发方法如何帮助创建新的治疗组合，了解经典组合治疗背后的定义原则及其背后的原始实验原理至关重要。其中一项原则是使用具有独立作用机制的联合疗法可以最大限度地减少耐药性的演变。另一个原因是，为了杀死足够的癌细胞来治愈患者，必须以最大耐受剂量递送多种药物——这种情况允许以可控的毒性增强癌细胞杀伤。鉴于这些模型，我们的目标是探索基于这些原则构建的联合方案耐药机制的最新基因组证据。有趣的是，我们发现新出现的基因组证据与早期从业者开发常用药物方案的一些基本原理相矛盾。然而，我们也发现，近期靶向治疗的加入并没有改变目前构建抗癌组合方案的基本原则，也没有在大多数癌症的治疗中取得实质性进展。我们建议新兴的系统/网络生物学方法有巨大的机会来影响成功药物方案的合理开发。具体来说，通过以多种方式检查药物组合，