Cooperation of oncogenic mutations in the control of malignancy

描述(由申请人提供)：癌症分子分析的主要动机之一是需要开发合理的方法来确定有效的癌症治疗方法。这需要发现癌细胞特异的药物靶点，以及临床经验表明的药物靶点组合。然而，目标识别是出了名的困难和不可预测。在一定程度上，这是因为细胞调节本身就很复杂。此外，肿瘤进展与控制细胞功能的遗传和代谢网络的深刻变化有关，这一点也变得很清楚。现在有广泛的共识，如果不考虑支持正常人类细胞功能的网络和恶性转化带来的变化，就不可能理解癌症的发展和进展。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对两个协同致癌突变的联合作用表现出协同反应。此外，我们还发现，这种“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，这表明致癌基因突变至少部分是通过汇聚信号机制诱导恶性细胞转化的。值得注意的是，这些基因可以在控制多种不同的细胞过程中发挥中介作用，如增殖、存活、运动和侵袭，这表明同时合作的癌基因突变可以通过有限数量的癌细胞特异性调控过程影响多种癌细胞特性。我们的实验方法允许对调控过程进行遗传和生化分析，通过考虑多个变量，协同致癌突变控制癌细胞的行为。在此背景下，我们重点分析了激活RAS和肿瘤抑制基因p53功能缺失突变之间的有效合作，这些突变经常在各种癌症中发现。我们的工作表明，p53功能的丧失通过改变信号整合事件深刻地影响RAS信号的传递质量，而信号整合事件在控制与恶性肿瘤相关的各种细胞属性方面发挥着关键作用。因此，我们假设，识别合作反应基因，以及研究它们的作用机制和功能相互关系，为识别癌细胞的脆弱性提供了一条合理的途径，特别是对于大部分对传统治疗方案特别耐药的P53缺陷癌症。

DESCRIPTION (provided by applicant): 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.