Comprehensive analysis of cancer genomes has provided important insights in the critical alterations that confer proliferation and survival advantage to the tumor, so-called driver mutations. Tumors harboring these genetic changes frequently exhibit striking sensitivities to inhibition of these oncogenic driver pathways, a principle referred to as oncogene addiction. Substantial progress has been made in the development of drugs that specifically target components of the pathways that are associated with these driver mutations. This has enabled the first steps in a shift from the use of cytotoxic drugs to highly selective targeted therapeutic agents for the treatment of cancer. Unfortunately, despite the expanding development of targeted anti-cancer strategies, treatment failure due to primary or acquired resistance is still an almost inevitable outcome in most advanced human cancers. Understanding drug resistance mechanisms will help design more efficient combination treatment strategies that help block resistance mechanisms before they become clinically manifest. In this review, we discuss how RNA interference functional genetic screens can be used to identify clinically relevant mechanisms of drug resistance and how this technology can be used to develop effective combination therapies.

中文翻译：

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通过功能基因筛查了解对靶向癌症药物的耐药性。

癌症基因组的全面分析为赋予肿瘤增殖和生存优势的关键改变（所谓的驱动突变）提供了重要的见识。带有这些遗传变化的肿瘤通常对抑制这些致癌驱动途径表现出惊人的敏感性，这一原理被称为致癌基因成瘾。在开发专门针对与这些驱动程序突变相关的途径组分的药物方面已取得了实质性进展。这使从使用细胞毒性药物向治疗癌症的高度选择性靶向治疗药物的转变迈出了第一步。遗憾的是，尽管针对性抗癌策略的发展日新月异，在大多数晚期人类癌症中，由原发性或获得性耐药引起的治疗失败仍然是几乎不可避免的结果。了解耐药机制将有助于设计更有效的联合治疗策略，从而有助于在耐药机制临床表现出来之前将其阻断。在这篇综述中，我们讨论了如何使用RNA干扰功能基因筛查来确定临床上耐药的相关机制，以及如何使用该技术来开发有效的联合疗法。