Targeting Lysosomal Vulnerabilities in Renal Pathogenesis

Project Summary/Abstract Autophagy is frequently upregulated in cancer cells under metabolic stress to recycle cellular components for protein and ATP synthesis to promote cell survival. Based on its important roles in maintaining cell viability and inducing resistance to radiation and chemotherapy, inhibition of autophagy has become a viable therapeutic approach that has been evaluated in clinical trials. However, there is a need to identify predictive biomarkers to enable selection of patients that may best respond to autophagy inhibitors. Our preliminary data demonstrates that the mTORC1 regulator REDD1 controls sensitivity to autophagy inhibition suggesting that cancers with significant REDD1 levels, such as renal cell carcinoma (RCC), are hypervulnerable to this therapeutic approach. Our major goal is to investigate the mechanisms that control sensitivity to autophagy inhibition in RCC cells to optimize its potential clinical application. In Aim 1, we will determine the role of REDD1 as a regulator of RCC pathogenesis and sensitivity to autophagy inhibition. In Aim 2, we will investigate the mechanistic link between PIM1 inhibition and upregulation of REDD1 with a focus on endoplasmic reticular stress. In Aim 3, we will evaluate the impact of clinically-relevant autophagy inhibitor-based combinations for RCC therapy.