Abstract
Tumour cells frequently utilize glutamine to meet bioenergetic and biosynthetic demands of rapid cell growth. However, glutamine dependence can be highly variable between in vitro and in vivo settings, based on surrounding microenvironments and complex adaptive responses to glutamine deprivation. Soft tissue sarcomas (STSs) are mesenchymal tumours where cytotoxic chemotherapy remains the primary approach for metastatic or unresectable disease. Therefore, it is critical to identify alternate therapies to improve patient outcomes. Using autochthonous STS murine models and unbiased metabolomics, we demonstrate that glutamine metabolism supports sarcomagenesis. STS subtypes expressing elevated glutaminase (GLS) levels are highly sensitive to glutamine starvation. In contrast to previous studies, treatment of autochthonous tumour-bearing animals with Telaglenastat (CB-839), an orally bioavailable GLS inhibitor, successfully inhibits undifferentiated pleomorphic sarcoma (UPS) tumour growth. We reveal glutamine metabolism as critical for sarcomagenesis, with CB-839 exhibiting potent therapeutic potential.
Highlights
Tumour cells frequently utilize glutamine to meet bioenergetic and biosynthetic demands of rapid cell growth
Soft tissue sarcomas (STSs) are a diverse group of malignancies arising from mesenchymal tissues, classified into >80 different subtypes based on their tissue of origin, genetic alterations, and age of occurrence[1,2]
We previously expanded upon this model with additional HIF-2α loss to generate LSL-KrasG12D/+;Trp53fl/fl; Epas1fl/fl (KPH2) animals, and determined HIF-2α surprisingly suppresses tumourigenesis[38] (Fig. 1b)
Summary
Tumour cells frequently utilize glutamine to meet bioenergetic and biosynthetic demands of rapid cell growth. Soft tissue sarcomas (STSs) are mesenchymal tumours where cytotoxic chemotherapy remains the primary approach for metastatic or unresectable disease. In contrast to previous studies, treatment of autochthonous tumour-bearing animals with Telaglenastat (CB-839), an orally bioavailable GLS inhibitor, successfully inhibits undifferentiated pleomorphic sarcoma (UPS) tumour growth. We reveal glutamine metabolism as critical for sarcomagenesis, with CB-839 exhibiting potent therapeutic potential. Cytotoxic chemotherapy typically represents the therapeutic approach for metastatic or unresectable STS, where 16% five-year survival rates are observed[9,10,11]. While substantial progress has revealed genetic features of distinct sarcoma subtypes[2,5,12], these diseases remain relatively understudied, making improved therapeutics necessary and challenging. Cancer cells typically rewire their metabolism to meet the bioenergetic and biosynthetic demands of uncontrolled cell growth[13,14,15]. BPTES’ moderate potency and low bioavailability limit clinical potential
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