Drug Repositioning for Clear Cell Renal Cell Carcinoma Based on Stratification of Patients

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common histological type of kidney cancer and has high molecular heterogeneity. Stratification of ccRCC is of importance since distinct subtypes can significantly differ in survival outcomes and treatment strategies. Here, we applied a systems biology approach to stratify ccRCC into three molecular subtypes with different mRNA expression patterns and prognosis of patients. Based on the relative expression orderings of genes (REOs), we further developed a set of classification biomarkers that could robustly classify the patients into each of the three subtypes and predict the prognosis of patients. Then, we reconstructed subtype-specific metabolic models and performed essential gene analysis to identify the potential drug targets for each subtype. We identified four potential drug targets, including SOAT1, CRLS1 and ACACB which were essential in all the three subtypes and GPD2 which was exclusively essential to subtype 1. Finally, we repositioned mitotane, a FDA approved SOAT1 inhibitor, for treatment of ccRCC and showed that it decreased tumor cell viability and inhibited tumor cell growth in in vitro experiments.

Keywords: kidney cancer; systems biology; biomarker; metabolic model; drug repositioning