Experimental Analysis and Computational Modeling of Network States and Drug Responses in the PI3K/Akt/mTOR Network

摘要

In breast cancer, the PI3K/Akt/mTOR and Ras/MEK/ERK signaling networks are believed to play a critical role in controlling tumor proliferation and survival, and thus are the main targets for a range of signaling inhibitors currently in clinical use or undergoing clinical trials. To make the most effective use of these inhibitors, we are developing quantitative models to predict inhibitor efficacy for individual patients based on the unique signaling states of the Akt and ERK networks. In the current report, we describe our identification of the cell cycle inhibitor p57Kip2 as a novel integration point between the ERK and Akt networks, and characterized the dynamics of p57Kip2 regulation in response to PI3K network activation in mammary epithelial cells. We also describe a newly constructed cell system for simultaneously measuring signaling and proliferation in real time in living cells. Data collected from this system are now being used to extend and refine our computational models.