Delineation of key regulatory elements identifies points of vulnerability in the mitogen-activated signaling network

Abstract

Drug development efforts against cancer are often hampered by the complex properties of signaling networks. Here we combined the results of an RNAi screen targeting the cellular signaling machinery, with graph theoretical analysis to extract the core modules that process both mitogenic and oncogenic signals to drive cell cycle progression. These modules encapsulated mechanisms for coordinating seamless transition of cells through the individual cell cycle stages and, importantly, were functionally conserved across different cancer cell types. Further analysis also enabled extraction of the core signaling axes that progressively guide commitment of cells to the division cycle. Importantly, pharmacological targeting of the least redundant nodes in these axes yielded a synergistic disruption of the cell cycle in a tissue-typeindependent manner. Thus, the core elements that regulate temporally distinct stages of the cell cycle provide attractive targets for the development of multi-module-based chemotherapeutic strategies. © 2011 by Cold Spring Harbor Laboratory Press.