Identifying strategies to target the metabolic flexibility of tumours

Abstract

<jats:title>Summary</jats:title><jats:p>Plasticity of cancer metabolism can be a major obstacle for efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify and quantify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that glutaminase isoform Gls2, expressed in normal liver, compensates for the deletion of Gls1 isoform expressed in tumours. Inhibiting both glutaminases significantly delays tumourigenesis but does not completely block glutamine catabolism through the Krebs cycle. We reveal that glutamine catabolism is then driven by amidotransferases. Consistently, the synergistic effect of glutaminase and amidotransferase inhibitors on proliferation of mouse and human tumour cells is observed <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>. Furthermore, when Gls1 is deleted the Krebs cycle activity and tumour formation can also be significantly affected if glycolysis is co-inhibited (Gls1<jats:sup>KO</jats:sup>/<jats:italic>Hk2<jats:sup>KO</jats:sup></jats:italic>). Finally, the inhibition of either serine (<jats:italic>Psat1</jats:italic><jats:sup>KO</jats:sup>) or fatty acid (<jats:italic>Fasn</jats:italic><jats:sup>KO</jats:sup>) biosynthesis can be compensated by uptake of circulating nutrients. Thus, removing these nutrients from the diet produces synergistic effects on suppression of tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate how targeting compensatory mechanisms can improve a therapeutic outcome.</jats:p>

Organelle Cooperation in Stem Cell Fate: Lysosomes as Emerging Regulators of Cell Identity

“…Many new and developing therapeutic strategies for cancer are directed toward targeting metabolic vulnerabilities of the tumor. Inhibition of lysosome activity by targeting autophagy signaling, using lysosomotropic agents like bafilomycin or chloroquine derivatives, or degradative capacity and ion transport are popular among these approaches (Nazio et al, 2019;Méndez-Lucas et al, 2020). Yet, despite the clear vulnerability of metabolic and lysosome-based networks in cancer, current lysosometargeted drugs have had limited success in clinical trials, often failing to provide adequate tumor-specific toxicity at least as single agents.…”