title: A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas.
abstract: Sarcomas comprise a large heterogeneous group of mesenchymal cancers with limited therapeutic options. When treated with standard cytotoxic chemotherapies, many sarcomas fail to respond completely and rapidly become treatment resistant. A major problem in the investigation and treatment of sarcomas is the fact that no single gene mutation or alteration has been identified among the diverse histologic subtypes. We searched for therapeutically druggable targets that are common to a wide range of histologies and hence could provide alternatives to the conventional chemotherapy. Seven hundred samples comprising 45 separate histologies were examined. We found that almost 90% were arginine auxotrophs, as the expression of argininosuccinate synthetase 1 was lost or significantly reduced. Arginine auxotrophy confers sensitivity to arginine deprivation, leading temporarily to starvation and ultimately to cell survival or death under different circumstances. We showed that, in sarcoma, arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20) maintains a prolonged state of arginine starvation without causing cell death. However, when starvation was simultaneously prolonged by ADI-PEG20 while inhibited by the clinically available drug chloroquine, sarcoma cells died via necroptosis and apoptosis. These results have revealed a novel metabolic vulnerability in sarcomas and provided the basis for a well-tolerated alternative treatment strategy, potentially applicable to up to 90% of the tumors, regardless of histology.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Bean
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Jeff C
authors.initials: JC
authors.lastname: Kremer
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Bethany C
authors.initials: BC
authors.lastname: Prudner
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schenone
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Juo-Chin
authors.initials: JC
authors.lastname: Yao
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Schultze
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: David Y
authors.initials: DY
authors.lastname: Chen
authors.affiliation: Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Munir R
authors.initials: MR
authors.lastname: Tanas
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.|Siteman Cancer Center, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Adkins
authors.affiliation: Polaris Group, San Diego, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Bomalaski
authors.affiliation: Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.|Siteman Cancer Center, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Loren S
authors.initials: LS
authors.lastname: Michel
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.|Siteman Cancer Center, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Van Tine
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000172:deficiency* / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000172:deficiency* / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D009336:Necrosis; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D011379:Prognosis; D012509:Sarcoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D000072020:Synthetic Lethal Mutations / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D011092:Polyethylene Glycols; D002738:Chloroquine; D001120:Arginine; D006867:Hydrolases; C512527:ADI PEG20; D001124:Argininosuccinate Synthase