Figure 1. Emerging resistance to arginine deprivation in cancer.

Several mechanisms may reduce the efficacy of arginine depleting enzymes for cancer therapy: (1) ASS1 upregulation; (2) autophagy; (3) stromal-tumor cell metabolic co-operation; (4) and anti-drug antibodies (e.g. to ADI-PEG 20). Some approaches to overcoming resistance include combining arginine depletors with chemotherapy, human (non-antigenic) arginases, and autophagy modulators such as chloroquine.