title: Inhibition of the Polyamine Synthesis Pathway Is Synthetically Lethal with Loss of Argininosuccinate Synthase 1.
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.
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Locke
authors.affiliation: Centre for Haemato-oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Essam
authors.initials: E
authors.lastname: Ghazaly
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Marta O
authors.initials: MO
authors.lastname: Freitas
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Mikaella
authors.initials: M
authors.lastname: Mitsinga
authors.affiliation: Laboratorio di Genetica Oncologica ed Oncologia Translazionale and Dipartimento di Oncologia, Azienda Ospedaliera S. Croce e Carle, 12100 Cuneo, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lattanzio
authors.affiliation: Laboratorio di Genetica Oncologica ed Oncologia Translazionale and Dipartimento di Oncologia, Azienda Ospedaliera S. Croce e Carle, 12100 Cuneo, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lo Nigro
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Ai
authors.initials: A
authors.lastname: Nagano
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Claude
authors.initials: C
authors.lastname: Chelala
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Szlosarek
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: sarah.martin@qmul.ac.uk.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Martin
mesh_terms: D001120:Arginine / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000172:deficiency* / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics; D008654:Mesothelioma / Q000235:genetics; D000086002:Mesothelioma, Malignant; D011073:Polyamines / Q000378:metabolism*; D011092:Polyethylene Glycols; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D011073:Polyamines; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C512527:ADI PEG20; D001124:Argininosuccinate Synthase