The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition

Justin Goodwin, Michael L. Neugent, Shin Yup Lee, Joshua H. Choe, Hyunsung Choi, Dana M. R. Jenkins, Robin J. Ruthenborg, Maddox W. Robinson, Ji Yun Jeong, Masaki Wake, Hajime Abe, Norihiko Takeda, Hiroko Endo, Masahiro Inoue, Zhenyu Xuan, Hyuntae Yoo, Min Chen, Jung-Mo Ahn, John D. Minna, Kristi L. Helke, Pankaj K. Singh, David B. Shackelford and Jung-whan Kim ()
Additional contact information
Justin Goodwin: The University of Texas at Dallas
Michael L. Neugent: The University of Texas at Dallas
Shin Yup Lee: The University of Texas at Dallas
Joshua H. Choe: The University of Texas at Dallas
Hyunsung Choi: The University of Texas at Dallas
Dana M. R. Jenkins: The University of Texas at Dallas
Robin J. Ruthenborg: The University of Texas at Dallas
Maddox W. Robinson: The University of Texas at Dallas
Ji Yun Jeong: School of Medicine, Kyungpook National University
Masaki Wake: The University of Tokyo
Hajime Abe: The University of Tokyo
Norihiko Takeda: The University of Tokyo
Hiroko Endo: Osaka International Cancer Institute
Masahiro Inoue: Osaka International Cancer Institute
Zhenyu Xuan: The University of Texas at Dallas
Hyuntae Yoo: The University of Texas at Dallas
Min Chen: The University of Texas at Dallas
Jung-Mo Ahn: The University of Texas at Dallas
John D. Minna: Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center
Pankaj K. Singh: The Eppley Institute for Cancer and Allied Diseases, Cell Biology and Anatomy, University of Nebraska Medical Center
David B. Shackelford: David Geffen, School of Medicine, University of California
Jung-whan Kim: The University of Texas at Dallas

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Adenocarcinoma (ADC) and squamous cell carcinoma (SqCC) are the two predominant subtypes of non-small cell lung cancer (NSCLC) and are distinct in their histological, molecular and clinical presentation. However, metabolic signatures specific to individual NSCLC subtypes remain unknown. Here, we perform an integrative analysis of human NSCLC tumour samples, patient-derived xenografts, murine model of NSCLC, NSCLC cell lines and The Cancer Genome Atlas (TCGA) and reveal a markedly elevated expression of the GLUT1 glucose transporter in lung SqCC, which augments glucose uptake and glycolytic flux. We show that a critical reliance on glycolysis renders lung SqCC vulnerable to glycolytic inhibition, while lung ADC exhibits significant glucose independence. Clinically, elevated GLUT1-mediated glycolysis in lung SqCC strongly correlates with high 18F-FDG uptake and poor prognosis. This previously undescribed metabolic heterogeneity of NSCLC subtypes implicates significant potential for the development of diagnostic, prognostic and targeted therapeutic strategies for lung SqCC, a cancer for which existing therapeutic options are clinically insufficient.

Date: 2017
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DOI: 10.1038/ncomms15503

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