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Cell Death Dis. 2016 Oct 13;7(10):e2406. doi: 10.1038/cddis.2016.232.

A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas.

Author information

1
Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
2
Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
3
Siteman Cancer Center, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
4
Polaris Group, San Diego, CA, USA.

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.

PMID:
27735949
PMCID:
PMC5133958
DOI:
10.1038/cddis.2016.232
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Dr. Brian Van Tine has a basic research grant from Polaris Pharmaceuticals. Dr. John Bomalaski is an employee of Polaris Pharmaceuticals, Inc. and holds stock options in Polaris Group. The remaining authors declare no conflict of interest.

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