Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Oncogene. 2013 Aug 15;32(33):3809-18. doi: 10.1038/onc.2012.389. Epub 2012 Sep 10.
Malignant cell transformation commonly results in the deregulation of thousands of cellular genes, an observation that suggests a complex biological process and an inherently challenging scenario for the development of effective cancer interventions. To better define the genes/pathways essential to regulating the malignant phenotype, we recently described a novel strategy based on the cooperative nature of carcinogenesis that focuses on genes synergistically deregulated in response to cooperating oncogenic mutations. These so-called 'cooperation response genes' (CRGs) are highly enriched for genes critical for the cancer phenotype, thereby suggesting their causal role in the malignant state. Here, we show that CRGs have an essential role in drug-mediated anticancer activity and that anticancer agents can be identified through their ability to antagonize the CRG expression profile. These findings provide proof-of-concept for the use of the CRG signature as a novel means of drug discovery with relevance to underlying anticancer drug mechanisms.
恶性细胞转化通常会导致数千个细胞基因的失调，这一观察结果表明这是一个复杂的生物学过程，对于开发有效的癌症干预措施来说，这是一个固有的挑战。为了更好地定义调控恶性表型所必需的基因/途径，我们最近描述了一种基于致癌作用的协同性质的新策略，该策略侧重于协同致癌突变反应中协同失调的基因。这些所谓的“合作反应基因”（CRGs）高度富集了对癌症表型至关重要的基因，从而提示它们在恶性状态中的因果作用。在这里，我们表明 CRGs 在药物介导的抗癌活性中起着至关重要的作用，并且可以通过它们拮抗 CRG 表达谱的能力来鉴定抗癌药物。这些发现为使用 CRG 特征作为一种新的药物发现方法提供了概念验证，该方法与潜在的抗癌药物机制相关。
