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

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

doi:10.1016/j.ccell.2018.04.002

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

Cancer Cell. 2018 May 14;33(5):905-921.e5. doi: 10.1016/j.ccell.2018.04.002.

Authors

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

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
² Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
³ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁴ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁵ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁶ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁷ Calithera Biosciences, South San Francisco, CA 94080, USA.
⁸ Memorial Care Health System, Long Beach, CA 90806, USA.
⁹ Hoag Memorial Hospital Presbyterian, Newport Beach, CA 92663, USA.
¹⁰ Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
¹¹ Department of Orthopedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
¹² Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
¹³ Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Thoracic Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
¹⁴ Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
¹⁵ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
¹⁶ Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: dshackelford@mednet.ucla.edu.

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.

Keywords: CB-839; GLS; GSK3α/β; PET imaging; glutaminolysis; glycolysis; lung squamous cell carcinoma; mTOR; metabolic signature.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Benzeneacetamides / administration & dosage*
Benzeneacetamides / pharmacology
Boron Compounds / administration & dosage*
Boron Compounds / pharmacology
Carcinoma, Squamous Cell / drug therapy
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Resistance, Neoplasm / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Glutamine / metabolism*
Glycine / administration & dosage
Glycine / analogs & derivatives*
Glycine / pharmacology
Glycogen Synthase Kinase 3 / metabolism*
Glycolysis
Humans
Ki-67 Antigen / genetics
Ki-67 Antigen / metabolism
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Mice
Neoplasm Transplantation
Signal Transduction / drug effects
Thiadiazoles / administration & dosage*
Thiadiazoles / pharmacology

Substances

Benzeneacetamides
Boron Compounds
CB-839
Ki-67 Antigen
MKI67 protein, human
MLN2238
Thiadiazoles
Glutamine
Glycogen Synthase Kinase 3
Glycine

Abstract

Publication types

MeSH terms

Substances

Grants and funding