ERG 245

We have previously demonstrated that BCAT1, the enzyme responsible for the reversible transamination of leucine in the cytosol, is a druggable target in immune-oncology: the small molecule inhibitor ERG245 dramatically increases the efficacy of anti-PD-1 treatment in the moderately immunogenic CT26 colon cancer model...Withdrawal of BCAT1 restored or reversed the cell phenotype leading to epigenetically altered CD8+ T cells with decreased histone acetyltransferase and histone demethylase presence, increased cytotoxicity, and increased ribosome biogenesis. Collectively, the data suggest that temporal inhibition of BCAT1 inhibition induces profound effects on CD8+ T cells including increased cytotoxicity and suppression of terminal exhaustion, thus rendering the cells rescuable by anti-PD-1 therapy.

Withdrawal of ERG245 restored intracellular lactate levels without reversing the metabolic reprogramming of the cells. We propose that these are elements of a mechanism that links temporal inhibition of BCAT1 to the rise of highly energetic CD8+ T cells with increased cytotoxicity and proliferative capacity in vitro and in vivo.