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

Gregory R Bean; Jeff C Kremer; Bethany C Prudner; Aaron D Schenone; Juo-Chin Yao; Matthew B Schultze; David Y Chen; Munir R Tanas; Douglas R Adkins; John Bomalaski; Brian P Rubin; Loren S Michel; Brian A Van Tine

doi:10.1038/cddis.2016.232

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

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

Gregory R Bean, Jeff C Kremer, Bethany C Prudner, Aaron D Schenone, Juo-Chin Yao, Matthew B Schultze, David Y Chen, Munir R Tanas, Douglas R Adkins, John Bomalaski, …

Cell death & disease, Vol.7(10), pp.e2406-e2406

10/2016

DOI: 10.1038/cddis.2016.232

PMCID: PMC5133958

PMID: 27735949

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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.

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Title: Subtitle: A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas
Creators: Gregory R Bean - , St. Louis, MO
Jeff C Kremer - , St. Louis, MO
Bethany C Prudner - , St. Louis, MO
Aaron D Schenone - , St. Louis, MO
Juo-Chin Yao - , St. Louis, MO
Matthew B Schultze - , St. Louis, MO
David Y Chen - , St. Louis, MO
Munir R Tanas - , Cleveland, OH
Douglas R Adkins - , St. Louis, MO
John Bomalaski - , San Diego, CA
Brian P Rubin - , Cleveland, OH
Loren S Michel - , St. Louis, MO
Brian A Van Tine - , St. Louis, MO
Resource Type: Journal article
Publication Details: Cell death & disease, Vol.7(10), pp.e2406-e2406
DOI: 10.1038/cddis.2016.232
PMID: 27735949
PMCID: PMC5133958
NLM abbreviation: Cell Death Dis
ISSN: 2041-4889
eISSN: 2041-4889
Publisher: Nature Publishing Group
Alternative title: Metabolic synthetic lethality in ASS1(-) sarcomas
Language: English
Date published: 10/2016
Academic Unit: Pathology
Record Identifier: 9984047668302771

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