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Published on: July 21, 2018
Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer
Kasey R Cargill1, C Allison Stewart1, Elizabeth M Park1
1Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Introduction:
The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches.
Methods:
We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3.
Results:
MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression.
Conclusions:
Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.
Insights
MYC overexpression in small cell lung cancer (SCLC) drives glycolysis. Inhibiting this pathway with PFK158 offers a potential therapeutic strategy for SCLC patients with high MYC expression.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Research
Background:
- MYC transcription factor is overexpressed in 30% of small cell lung cancer (SCLC) tumors.
- MYC influences the balance between glycolysis and mitochondrial respiration in SCLC.
Purpose of the Study:
- Investigate MYC's role in SCLC metabolism.
- Identify potential metabolic targeting strategies for SCLC.
Main Methods:
- Analyzed transcriptional and metabolomics data based on cMYC expression.
- Assessed metabolic pathway utilization using flow cytometry and Seahorse extracellular flux.
- Evaluated glycolysis inhibition in vitro and in vivo with PFK158.
Main Results:
- MYC overexpression correlated with increased glycolysis gene expression in SCLC.
- MYC-high SCLC cells showed enhanced glycolysis (Warburg effect); MYC-low cells relied more on oxidative metabolism.
- PFK158 treatment reduced glucose uptake, ATP, and lactate in MYC-high SCLC cells and delayed tumor growth in vivo.
Conclusions:
- SCLC metabolic programming is characterized by MYC-driven glycolysis.
- Glycolysis is a targetable mechanism in a subset of SCLC patients.
- PFK158 demonstrates therapeutic potential for MYC-driven SCLC.
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