Cooperation of oncogenic mutations in the control of malignancy

癌症分子分析的主要动机之一是需要发展合理的 确定有效癌症治疗方法的方法。这需要发现癌细胞-- 具体的药物靶点，以及临床经验表明的药物靶点组合。目标识别， 然而，这是出了名的困难和不可预测。在一定程度上，这是因为细胞调节天生就是 很复杂。此外，肿瘤的进展也已变得明显与显著的 控制细胞功能的遗传和代谢网络的变化。现在有广泛的 共识是，如果不了解癌症的发展和进展，就不可能 对支持正常人类细胞功能的网络及其带来的变化的思考 大约是通过恶变。 在我们专注于多步骤致癌的分子机制的研究中，我们 已经确定了一组细胞基因，这些基因在表达或蛋白质活性方面显示出协同作用 对两个协同致癌突变的联合作用的反应。此外，我们还证明了这样的 “协同反应基因”对于癌细胞表型的表达和维持是必不可少的。 表明致癌基因突变至少部分地通过聚合诱导恶性细胞转化 信令机制。值得注意的是，这些基因可以在多重和多样性的控制中发挥中介作用。 细胞过程，如增殖、存活、运动性和侵袭性，表明合作 癌基因突变可以通过有限数量的癌症同时影响多个癌细胞的特征 特定于细胞的调控过程。 我们的实验方法允许通过以下方式对调控过程进行遗传和生化分析 哪些协同致癌基因突变通过考虑多个 变量。在此背景下，我们重点分析了激活RAS与肿瘤之间的强大合作 抑癌基因P53功能缺失突变常见于多种癌症。我们的工作揭示了 P53功能的丧失通过改变信号而深刻地影响RAS信号的传递质量 整合事件在控制与恶性肿瘤相关的各种细胞特性方面发挥关键作用。我们 因此，假设合作反应基因的识别和它们的研究 作用机制和功能相互关系为鉴定癌细胞提供了一条合理的途径 脆弱性，特别是对于大部分具有P53缺陷的癌症来说，这些缺陷对 常规治疗方案。

One of the main motives for the molecular analysis of cancer is the need to develop rational approaches to the identification of effective cancer treatments. This requires the discovery of cancer cell- specific drug targets and, as clinical experience indicates, drug target combinations. Target identification, however, is notoriously difficult and unpredictable. In part, this is because cell regulation is inherently complex. In addition, it has also become clear that neoplastic progression is associated with profound changes in the genetic and metabolic networks that control the functioning of the cell. There is now broad consensus that it will be impossible to understand the development and progression of cancer without consideration of the networks that support functioning of the normal human cell and the changes brought about by malignant transformation. In our research focusing on the molecular mechanisms underlying multi-step carcinogenesis, we have identified sets of cellular genes that with regard to their expression or protein activity show synergistic responses to the combined action of two cooperating oncogenic mutations. Moreover, we show that such 'cooperation response genes' can be essential for expression and maintenance of the cancer cell phenotype, indicating that oncogenic mutations induce malignant cell transformation at least in part through converging signaling mechanisms. Remarkably, these genes can act as mediators in the control of multiple and diverse cellular processes, such as proliferation, survival, motility and invasiveness, suggesting that cooperating oncogenic mutations simultaneously can affect multiple cancer cell traits through a limited number of cancer cell-specific regulatory processes. Our experimental approach permits genetic and biochemical analysis of the regulatory processes by which cooperating oncogenic mutations control cancer cell behavior through consideration of multiple variables. In this context we focus on analysis of the potent cooperation between activating Ras and tumor suppressor p53 loss-of-function mutations frequently found in a variety of cancers. Our work has revealed that loss of p53 function profoundly affects the quality of Ras signal transmission through altering signal integration events that play key roles in controlling various cell properties associated with malignancy. We thus hypothesize that identification of cooperation response genes together with investigation of their mechanisms of action and functional inter-relationships provides a rational path to identification of cancer cell vulnerabilities, particularly for the large fraction of cancers with defective p53 that are particularly resistant to conventional treatment regimens.