Synthetic Lethality and Extracellular Vesicle Metabolism in Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common kidney tumor, and its incidence continues to rise. Elucidation of the molecular biology and the tumor microenvironment (TME) have revolutionized the treatment landscape of ccRCC in the past few decades. Although loss of von Hippel-Lindau is the initiating event in ccRCC tumorigenesis, subsequent studies have shown that mutations in other driver genes are required, including chromatin modifiers such as SET containing domain 2 (SETD2). We show here that we can exploit SETD2-mutant ccRCC tumors by treating them with PI3KBeta and AKT inhibitors, which hindered growth in vitro and in vivo. Activation of the PI3K/AKT signaling pathway is associated with aggressive tumor behavior and leads to metabolic reprogramming in cancer cells. Furthermore, we found that extracellular vesicles (EVs), which are emerging players in cell-to-cell communication in the TME, released from ccRCC cells treated with anti-angiogenic agents exhibit higher glycolytic activity by secreting more glucose transporter 1 into their vesicles. These metabolically active EVs may be competing for nutrients with immune cells in the TME, which would present a distinct metabolic barrier to immune cell function and possibly impede immunotherapy efficacy.