The GSK3 Signaling Axis Regulates Adaptive Glutamine Metabolism in Lung Squamous Cell Carcinoma

Publication date: 14 May 2018
Source:Cancer Cell, Volume 33, Issue 5
Author(s): Milica Momcilovic, Sean T. Bailey, Jason T. Lee, Michael C. Fishbein, Daniel Braas, James Go, Thomas G. Graeber, Francesco Parlati, Susan Demo, Rui Li, Tonya C. Walser, Michael Gricowski, Robert Shuman, Julio Ibarra, Deborah Fridman, Michael E. Phelps, Karam Badran, Maie St. John, Nicholas M. Bernthal, Noah Federman, Jane Yanagawa, Steven M. Dubinett, Saman Sadeghi, Heather R. Christofk, David B. Shackelford
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.

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Teaser

By performing in vivo metabolic profiling of lung squamous cell carcinoma (LSCC), Momcilovic et al. identify upregulation of glutaminolysis as a mechanism of adaptation to suppression of glycolysis upon mTOR inhibition. Several LSCC mouse models are sensitive to combined inhibition of mTOR and glutaminase.


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