Defining the Role of Autophagy Kinase ULK1 Signaling in Therapeutic Response of Tuberous Sclerosis Complex to mTOR Inhibitors

The Tuberous Sclerosis Complex tumor suppressors are known to be critical negative regulators of the mTORC1 kinase complex that controls cell growth and autophagy. Our laboratory and others have recently decoded a major conserved route that mTORC1 uses to control autophagy. These studies demonstrate that mTORC1 inactivatesanother kinase complex composed of the autophagy kinase ULK1 and its associated subunits. One prediction of these findings is that in cells and tumors with TSC mutations and hyperactive mTOR, the ULK1 complex and the process of autophagy will be suppressed. There were two major aims for this funding period 1 to further developantibodies and reagents to readout ULK1-activity and substrate phosphorylation to see how well they act as biomarkers of mTOR inhibition, and 2 to further explore use of novel small molecule inhibitors of ULK1 to synergize with mTOR inhibitors to induce cell death.