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

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 andmetabolomic 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.