| Literature DB >> 29763624 |
Milica Momcilovic1, Sean T Bailey1, Jason T Lee2, Michael C Fishbein3, Daniel Braas4, James Go5, Thomas G Graeber6, Francesco Parlati7, Susan Demo7, Rui Li1, Tonya C Walser1, Michael Gricowski8, Robert Shuman8, Julio Ibarra8, Deborah Fridman9, Michael E Phelps2, Karam Badran10, Maie St John10, Nicholas M Bernthal11, Noah Federman12, Jane Yanagawa13, Steven M Dubinett14, Saman Sadeghi5, Heather R Christofk15, David B Shackelford16.
Abstract
Altered metabolism is a hallmark of cancer growth, forming the conceptual basis for development of metabolic therapies as cancer treatments. We performed in vivo metabolic profiling and molecular analysis of lung squamous cell carcinoma (SCC) to identify metabolic nodes for therapeutic targeting. Lung SCCs adapt to chronic mTOR inhibition and suppression of glycolysis through the GSK3α/β signaling pathway, which upregulates glutaminolysis. Phospho-GSK3α/β protein levels are predictive of response to single-therapy mTOR inhibition while combinatorial treatment with the glutaminase inhibitor CB-839 effectively overcomes therapy resistance. In addition, we identified a conserved metabolic signature in a broad spectrum of hypermetabolic human tumors that may be predictive of patient outcome and response to combined metabolic therapies targeting mTOR and glutaminase.Entities:
Keywords: CB-839; GLS; GSK3α/β; PET imaging; glutaminolysis; glycolysis; lung squamous cell carcinoma; mTOR; metabolic signature
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Year: 2018 PMID： 29763624 PMCID： PMC6451645 DOI： 10.1016/j.ccell.2018.04.002
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 38.585