Arginine Deprivation in Sarcoma as a Therapeutic Strategy
The vast majority of sarcomas lack a functional level of the enzyme argininosuccinate synthetase 1 (ASS1), which is required for synthesis of arginine. This deficiency renders these sarcomas auxotrophic for arginine. The enzymatic drug PEGylated arginine deiminase (ADI-PEG20) can be used to degrade extracellular arginine to citrulline, thereby starving ASS1-deficient cells. This causes a drastic reduction in growth rate and may lead to death in some cells. However, many sarcomas gain resistance after a period of metabolic adaptation. This resistance is marked by increased expression of ASS1, as the gene is rarely mutated or deleted, but rather reversibly repressed in these cancers. Because arginine deprivation is not sufficient to kill these cells, we are studying cellular responses to ADI-PEG20 treatment in order to identify new pathways to target in combination with arginine deprivation to cause death before cancer cells gain resistance. To investigate the effect of ADI-PEG20 on gene expression, we used the nCounter® Metabolic Pathways Panel to profile SKLMS1 human sarcoma cells with and without 72 hours of ADI-PEG20 treatment, the point at which these cells begin to gain resistance and grow faster.
For Research Use Only. Not for Use in Diagnostic Procedures.