Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma
Year: 2015
Type: article
Abstract: Current therapies for sarcomas are often inadequate. This study sought to identify actionable gene targets by selective targeting of the molecular networks that support sarcoma cell proliferation. Silencing of asparagine synthetase (ASNS), an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic Kras and disruption of Cdkn2a. ASNS silencing in mouse and human sarcoma cell lines reduced the percentage of S phase cells and impeded new polypeptide synthesis. These effects of ASNS silencing were reversed by exogenous supplementation with asparagine. Also, asparagine depletion via the ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase inhibited mouse and human sarcoma growth in vitro, and genetic silencing of ASNS in mouse sarcoma cells combined with depletion of plasma asparagine inhibited tumor growth in vivo. Asparagine reliance of sarcoma cells may represent a metabolic vulnerability with potential anti-sarcoma therapeutic value.
Source: eLife
DOI: 10.7554/elife.09436
Institutions: Joslin Diabetes Center, Harvard University, University of Freiburg, University Medical Center Freiburg, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Charité – Universitätsmedizin Berlin, Broad Institute, University of Maryland, Baltimore County, Tufts University, Indiana University – Purdue University Indianapolis
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: American Association for Cancer Research, Sarcoma Foundation of America, St. Baldrick's Foundation, Joslin Diabetes Center, Dana-Farber Cancer Institute, National Institute for Health and Care Research, National Institutes of Health, Harvard Stem Cell Institute, Stand Up To Cancer, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W2216762807