PQ - 22 Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene? Background: The viability of cancer cells is dependent on the continued production and activity of various pro-oncogenic proteins. In some cases, when therapies target these oncoproteins, individual tumor cells may die abruptly. This process is often called "oncogene addiction," and rapid regression of several tumor types with targeted therapies has been seen in patients. While this cell death is an encouraging outcome for therapeutic approaches, we have little knowledge of why these cells become so strongly dependent on the continued expression of an active mutated oncogene, particularly because the initiating cells often express the normal proto-oncoprotein. This Provocative Question asks why tumor cells die so rapidly when the addicting oncoprotein is depleted or its enzymatic activity blocked by a targeted therapy. Feasibility: Many examples of oncogene-dependence, both in human cancers and mouse models of cancer, are now subjects of great interest, because the “addicting” oncogene products are promising targets for modern cancer therapy. The signaling networks in which they are active are also being studied to identify other therapeutic targets. Modern molecular biological methods focused on protein function should be useful in studying why cells become addicted to these oncoproteins and die so rapidly when they are lost. Implications of success: Knowledge of how a cell develops vulnerability to the loss an oncogenic protein, and undergoes programmed cell death in consequence, would likely suggest additional novel targets for therapy. In addition, it might offer insight into the question of which tumors are most susceptible to targeted therapies and the problem of eliminating all cells in a tumor with such therapies. |
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