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Published on: July 21, 2018
Identifying strategies to target the metabolic flexibility of tumours
Andrés Méndez-Lucas1, Wei Lin1, Paul C Driscoll1
1The Francis Crick Institute, London, UK.
Abstract:
Plasticity of cancer metabolism can be a major obstacle to efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that, while inhibition of both glutaminase isoforms (Gls1 and Gls2) in tumours considerably delays tumourigenesis, glutamine catabolism continues, owing to the action of amidotransferases. Synergistic inhibition of both glutaminases and compensatory amidotransferases is required to block glutamine catabolism and proliferation of mouse and human tumour cells in vitro and in vivo. Gls1 deletion is also compensated for by glycolysis. Thus, co-inhibition of Gls1 and hexokinase 2 significantly affects Krebs cycle activity and tumour formation. Finally, the inhibition of biosynthesis of either serine (Psat1-KO) or fatty acid (Fasn-KO) is compensated for by uptake of circulating nutrients, and dietary restriction of both serine and glycine or fatty acids synergistically suppresses tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate that either pharmacological or dietary targeting of metabolic compensatory mechanisms can improve therapeutic outcomes.
Insights
Cancer cells adapt their metabolism to survive. Targeting compensatory pathways, like glutamine metabolism and glycolysis, alongside primary targets, is crucial for effective cancer therapy and tumor suppression. Dietary changes also show promise.
Area of Science:
- Oncology
- Cancer Metabolism
- Tumorigenesis
Background:
- Cancer cell metabolism is highly adaptable, presenting challenges for targeted therapies.
- Understanding compensatory mechanisms in cancer metabolism is key to overcoming treatment resistance.
Purpose of the Study:
- To identify compensatory metabolic pathways in c-MYC-induced liver tumors after inhibition of central carbon metabolism.
- To evaluate synergistic therapeutic strategies targeting these compensatory mechanisms.
Main Methods:
- Inhibition of glutaminase isoforms (Gls1, Gls2) and amidotransferases in mouse and human tumor cells.
- Genetic deletion of Gls1 and co-inhibition with hexokinase 2.
- Investigating nutrient uptake and dietary restriction effects in Psat1-KO and Fasn-KO models.
Main Results:
- Inhibition of glutaminases delays tumorigenesis but is compensated by amidotransferases; synergistic inhibition blocks proliferation.
- Gls1 deletion is compensated by glycolysis; co-inhibition with hexokinase 2 impacts Krebs cycle and tumor formation.
- Inhibition of serine or fatty acid biosynthesis is compensated by nutrient uptake; dietary restriction synergistically suppresses tumors.
Conclusions:
- Tumor metabolism exhibits significant flexibility, utilizing compensatory pathways to evade targeted inhibition.
- Combined targeting of primary metabolic vulnerabilities and compensatory mechanisms, through pharmacological or dietary interventions, can enhance therapeutic outcomes in cancer treatment.
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