Project Summary/AbstractAutophagy is frequently upregulated in cancer cells under metabolic stress to recyclecellular components for protein and ATP synthesis to promote cell survival. Based on itsimportant roles in maintaining cell viability and inducing resistance to radiation andchemotherapy inhibition of autophagy has become a viable therapeutic approach that hasbeen evaluated in clinical trials. However there is a need to identify predictive biomarkersto enable selection of patients that may best respond to autophagy inhibitors. Ourpreliminary data demonstrates that the mTORC1 regulator REDD1 controls sensitivity toautophagy inhibition suggesting that cancers with significant REDD1 levels such as renalcell carcinoma (RCC) are hypervulnerable to this therapeutic approach. Our major goalis to investigate the mechanisms that control sensitivity to autophagy inhibition in RCCcells to optimize its potential clinical application. In Aim 1 we will determine the role ofREDD1 as a regulator of RCC pathogenesis and sensitivity to autophagy inhibition. In Aim2 we will investigate the mechanistic link between PIM1 inhibition and upregulation ofREDD1 with a focus on endoplasmic reticular stress. In Aim 3 we will evaluate the impactof clinically-relevant autophagy inhibitor-based combinations for RCC therapy.