Abstract 1187: Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma

Abstract

Abstract Background. Currently available therapies for sarcomas are often inadequate. This study sought to identify actionable gene targets in sarcomas by selective targeting of the molecular networks that support sarcoma cell proliferation. Experimental approach. Mouse sarcomas driven by expression of oncogenic Kras(G12v) and disruption of CDKN2A (p16p19) were induced by ex-vivo transduction and intramuscular injection of mouse satellite cells. Kras; p16p19null sarcomas identified a cluster of genes upregulated in mouse sarcomas and human rhabdomyosarcoma compared to normal skeletal muscle. A customized shRNA proliferation screen was used to identify transcripts within this cluster that reduced sarcoma cell proliferation. Target gene effects on sarcoma growth were evaluated in mouse and human sarcoma cell lines and xenografts. Results. 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 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. Conclusions. The generation of new protein mass by rapidly proliferating sarcoma cells requires adequate Asparagine availability. Asparagine reliance of sarcoma cells may represent an actionable, metabolic vulnerability with potential anti-rhabdomyosarcoma therapeutic value. Citation Format: Simone Hettmer, Anna C. Schinzel, Daria Tchessalova, Nigel GJ Richards, William C. Hahn, Amy J. Wagers. Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1187. doi:10.1158/1538-7445.AM2015-1187