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Decoding and targeting the PI3K-mTOR signaling network in cancer

Brendan D. Manning

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National Institutes of Health (NIH)
Decoding and targeting the PI3K-mTOR signaling network in cancer The major growth factor signaling pathways in normal cells (e.g., PI3K and RAS) are also the ones that are most frequently genetically activated in cancer cells, leading to cell autonomous growth and proliferation. mTOR complex 1 (mTORC1) is a major driver of cell growth and is aberrantly activated in the majority of human cancers. This activation occurs through a network of upstream oncogenes and tumor suppressors that converge on a small G protein switch directly upstream of mTORC1. This switch involves the tuberous sclerosis complex (TSC) tumor suppressors, which form a protein complex (the TSC complex) that regulates a member of the Ras family of GTPases, called Rheb, an essential direct activator of mTORC1. Our previous studies have found that the TSC complex and Rheb serve as the key molecular link between the PI3K pathway and mTORC1 signaling. Over the past decade, our laboratory has been at the forefront of major discoveries regarding the PI3K-mTOR signaling network and its role in both normal cellular physiology and the aberrant growth of tumor cells. This grant is focused on defining the complex wiring of the oncogenic signaling network upstream of the TSC complex and mTORC1 and the downstream consequences stemming from the common dysregulation of this network in human cancers. The research plan builds on our breakthrough findings from the past 5 years in two major areas: 1) Upstream signaling - To define the molecular regulation of the TSC- Rheb-mTORC1 circuit as a shared target of multiple oncogenic signaling pathways and its role in the development of resistance to targeted therapeutics acting on these upstream pathways; 2) Downstream consequences - To delineate the critical metabolic and adaptive response processes controlled by the PI3K- mTOR pathway that underlie the uncontrolled growth and survival of cancer cells and therapeutic opportunities arising from manipulation of these processes. These collective studies emphasize the need to gain a deep understanding of the molecular wiring of this ubiquitous signaling network and how it interfaces with key cellular processes in order to reveal novel vulnerabilities that can be exploited to selectively kill cancer cells, the majority of which exhibit perturbations in the contol of this network.

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