Targeting Branched-Chain Amino Acid Transamination Sensitizes Clear Cell Renal Cell Carcinoma to Glutaminase Inhibition

Metabolic reprogramming is a well-described hallmark of clear cell renal cell carcinoma (ccRCC). Gene copy number variation and altered gene expression data suggest enhanced branched-chain amino acid (BCAA) transamination and reduced BCAA oxidation are highly selected traits in ccRCC. Surprisingly, we found that genetic modulation of BCAA oxidation had little effect on experimental ccRCC cell growth in vitro and in vivo. In contrast, BCAA transamination in ccRCC cells was essential for the generation of glutamate-derived glutathione and cell viability when glutamine was limiting. Thus, BCAA transamination conferred resistance to states of low glutamine or treatment with the glutaminase inhibitor CB-839 by providing glutathione independent of glutamine breakdown. Targeting BCAA transamination in vitro and in vivo sensitized ccRCC to CB-839 mediated glutaminase inhibition by decreasing glutathione biosynthesis and redox homeostasis. These findings reveal that BCAA transamination maintains critical glutamate and glutathione levels in glutamine-deprived ccRCC, explaining why CB-839 treatment has been ineffective in ccRCC clinical trials and demonstrate an approach to treat ccRCC by targeting BCAA transamination to create a vulnerability to glutaminase inhibition.