Editors' ChoiceCancer

Serving cancer its last meal

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Science Translational Medicine  08 Nov 2017:
Vol. 9, Issue 415, eaaq1233
DOI: 10.1126/scitranslmed.aaq1233

Abstract

Abolishment of just one of the pathways activated by mTORC1 creates a metabolic imbalance that drives cancer cell death.

Tumor cells are known to alter their metabolic activity to maintain a proliferative state and to survive under stressful microenvironmental conditions. Anabolic pathways are activated to produce the biomass necessary for continued cellular growth but the usage of cellular resources must be balanced so that all the required macromolecules can be produced. In a recent report, Valvezan et al. describe a targeting strategy that uncouples the downstream pathways of a key metabolic enzyme called mechanistic target of rapamycin complex 1 (mTORC1), creating an anabolic imbalance that the cancer cells cannot handle.

mTORC1 promotes the biosynthesis of proteins, lipids, and nucleotides. In the context of a continually proliferating and expanding tumor, maintaining a pipeline of these components is critical, and indeed mTORC1 is commonly activated in cancer. Inactivation of a complex that normally inhibits mTORC1 results in sporadic tumors in patients with the genetic disorder tuberous sclerosis complex (TSC). Small molecule inhibitors that target mTORC1, such as rapamycin, are useful in tempering the growth of tuberous sclerosis tumors, but the tumors grow back once treatment is stopped. The authors speculated that because these inhibitors prevent all mTORC1 activity, their use may inadvertently sustain an anabolic balance within the cancerous cells, instead of creating an imbalance that would be unviable. To test this, they used pharmacological agents such as mizoribine that stop mTORC1-stimulated nucleotide synthesis but still allow mTORC1 to drive ribosome biogenesis. In cell lines and multiple mouse models of TSC, mizoribine treatment led to an increase in tumor cell death, which the authors went on to demonstrate was induced by replication stress caused by the resulting limited nucleotide pool. Since mTORC1 was still able to promote ribosomal RNA synthesis, this left fewer nucleotides available for DNA synthesis and hence an increase in DNA damage that drove the cells to die. Importantly, as normal cells lacked the increased activation of mTORC1, they were not as impacted by this treatment approach.

Future studies will be needed to validate the utility of this metabolic uncoupling approach in other tumors with elevated mTORC1. This work highlights the power of connecting basic research with clinical translation to identify unique points of fragility in cancer .

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