Fig. 8.

The schematic diagram illustrates several mechanisms leading to sensitivity to arginine deprivation/ADI-PEG20 treatment in BR cells. BRAFi resistance downregulates c-Myc-mediated ASS1 transcription; hence, BR cells are arginine auxotrophic. Moreover, upregulated E3 ligase RNF44 also promotes AMPK-α1 degradation which abrogates autophagic flux, impairs glucose uptake and glycolysis, and enhances expression of arginine transporter 2 (CAT-2). These biological alterations switch metabolism toward exogenous arginine addiction and consequently give rise to an increase in vulnerability to arginine deprivation in BR cells.