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

Abstract

SummaryArgininosuccinate 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.

Spermidine Suppresses Inflammatory DC Function by Activating the FOXO3 Pathway and Counteracts Autoimmunity

“…Interestingly, the derivates of L-arginine exhibited different changes in the two processes. L-arginine metabolic pathway consists of the L-arginine-nitric oxide (NO) pathway and polyamine catabolism pathway (Babicova et al, 2011;Locke et al, 2016;Mondanelli et al, 2017). As the major components of polyamine catabolism (Locke et al, 2016), both spermidine and spermine decreased during IFN priming and following TLR7 ligand stimulation ( Figures 1B and 1C).…”

Targeting Metabolism for Cancer Therapy

“…Whether some tumors are more dependent on loss of ASS1 expression to proliferate is an area of active investigation, as these may be more responsive to arginine depleting drugs. The combination of arginine depletion with other therapies might also limit resistance, and the identification of synthetic lethal targets with ASS1-loss is another approach being evaluated to increase the clinical efficacy of therapies that deplete circulating arginine (Bean et al, 2016; Kremer et al, 2017; Locke et al, 2016). …”

Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors

“…Due to downregulation of arginine biosynthesis enzymes, argininosuccinate synthetase 1 (ASS1), ornithine transcarbamylase and/or argininosuccinate lyase, cancers like hepatocellular carcinoma, melanoma, renal cell and prostate cancers become auxotrophic for arginine and susceptible to arginine-depletion therapies (Patil et al, 2016; Phillips et al, 2013). Arginine depletion in ASS1-deficient cancer cells resulted in reduced polyamine levels and synthetic lethality (Locke et al, 2016). Likewise, ASS1 plays an important role in T cells as ASS1 deficiency reduced differentiation and numbers of peripheral T cells, which may explain the sensitivity of T cells to arginase (Tarasenko et al, 2015).…”