Inhibition of the Polyamine Synthesis Pathway Is Synthetically Lethal with Loss of Argininosuccinate Synthase 1

Cell Rep. 2016 Aug 9;16(6):1604-1613. doi: 10.1016/j.celrep.2016.06.097. Epub 2016 Jul 21.

Abstract

Argininosuccinate synthase 1 (ASS1) is the rate-limiting enzyme for arginine biosynthesis. ASS1 expression is lost in a range of tumor types, including 50% of malignant pleural mesotheliomas. Starving ASS1-deficient cells of arginine with arginine blockers such as ADI-PEG20 can induce selective lethality and has shown great promise in the clinical setting. We have generated a model of ADI-PEG20 resistance in mesothelioma cells. This resistance is mediated through re-expression of ASS1 via demethylation of the ASS1 promoter. Through coordinated transcriptomic and metabolomic profiling, we have shown that ASS1-deficient cells have decreased levels of acetylated polyamine metabolites, together with a compensatory increase in the expression of polyamine biosynthetic enzymes. Upon arginine deprivation, polyamine metabolites are decreased in the ASS1-deficient cells and in plasma isolated from ASS1-deficient mesothelioma patients. We identify a synthetic lethal dependence between ASS1 deficiency and polyamine metabolism, which could potentially be exploited for the treatment of ASS1-negative cancers.

MeSH terms

  • Arginine / metabolism
  • Argininosuccinate Synthase / deficiency*
  • Argininosuccinate Synthase / genetics*
  • Cell Line, Tumor
  • DNA Methylation / genetics
  • Humans
  • Hydrolases / genetics*
  • Lung Neoplasms / genetics
  • Mesothelioma / genetics
  • Mesothelioma, Malignant
  • Polyamines / metabolism*
  • Polyethylene Glycols
  • Promoter Regions, Genetic / genetics

Substances

  • Polyamines
  • Polyethylene Glycols
  • Arginine
  • Hydrolases
  • ADI PEG20
  • Argininosuccinate Synthase