PEG-BCT-100 and Canavanine Synergistically Induce Apoptosis in Arginine Biosynthetic Enzyme-Deficient Pancreatic Cancer.

[ABSTRACT] Arginine deprivation using arginase emerges as a potential cancer treatment approach, as some cancers have been found to be arginine-auxotrophic, relying on exogenous arginine for their growth. In this study, we evaluated the combination of a PEGylated recombinant human arginase (PEG-BCT-100), which is currently undergoing clinical trials, with a toxic arginine analog, canavanine, in pancreatic cancer. Remarkable synergistic antitumor effect was observed both in vitro and in vivo. Specifically, the combination treatment induced apoptotic cell death in pancreatic cancer cells, whereas normal fibroblast cells remained viable. Our findings also suggested that pancreatic tumors lacking the key enzymes in arginine biosynthesis, argininosuccinate synthetase 1 (ASS1) and ornithine transcarbamylase (OTC), were more susceptible to the treatment. From our in-house cohort and online database analysis, we found that the majority of the patients with pancreatic cancer exhibited deficiencies in both ASS1 and OTC enzymes, suggesting that the combination of arginine deprivation and canavanine could be particularly effective in these patients. The ASS1 and OTC negativity could also serve as predictive biomarkers for the response in other arginine-dependent cancers.

[SIGNIFICANCE] This study investigates the synergistic antitumor effect of PEG-BCT-100, an arginase, in clinical trials, with canavanine in pancreatic cancer, in vitro and in vivo. The treatment induces cancer cell apoptosis while sparing normal fibroblasts. Our findings suggest heightened susceptibility of pancreatic tumors deficient in arginine biosynthesis enzymes ASS1 and OTC.