Cooperation of oncogenic mutations in the control of malignancy

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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.