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Amino Acid Metabolism in Hematologic Malignancies and the Era of Targeted Therapy

Yoko Tabe, Philip L. Lorenzi and Marina Konopleva

Abstract

Tumor cells rewire metabolic pathways to adapt to their increased nutritional demands for energy, reducing equivalents, and cellular biosynthesis. Alternations in amino acid metabolism are one modality for satisfying those demands. Amino acids are not only components of proteins but also intermediate metabolites fueling multiple biosynthetic pathways. Amino acid-depletion therapies use heterologous enzymes or recombinant or engineered human enzymes to decrease the concentration of amino acids upon which tumor cells have become dependent for survival. Notably, such therapies have minimal effect on normal cells due to their ability to synthesize the targeted amino acids under conditions of nutrient stress. Here we review novel aspects of amino acid metabolism in hematologic malignancies and deprivation strategies using heterologous or engineered enzymes, focusing on four key amino acids: arginine, asparagine, glutamine, and cysteine. We also present the roles of amino acid metabolism in the immunosuppressive tumor microenvironment and in drug resistance, and we present an argument for the reclassification of amino acid-depleting enzymes as targeted therapies.

  • Submitted May 20, 2019.
  • Revision received August 14, 2019.
  • Accepted August 3, 2019.