Metabolic Reprogramming by c-MET Inhibition as a Targetable Vulnerability in Glioblastoma.

Trang Thi Thu Nguyen,Georg Karpel-Massler,Markus D Siegelin,Enyuan Shang

doi:10.18632/oncoscience.498

Trang Thi Thu Nguyen, Georg Karpel-Massler + Show 2 more

Open Access

https://doi.org/10.18632/oncoscience.498

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Abstract

The elucidation of better treatments for solid tumors and especially malignant glial tumors is a priority. Better understanding of the molecular underpinnings of treatment response and resistance are critical determinants in the success for this endeavor. Recently, a battery of novel tools have surfaced that allow to interrogate tumor cell metabolism to more precise extent than this was possible in the earlier days. At the forefront of these developments are the extracellular flux and carbon tracing analyses. Through utilization of these techniques our group made the recent observation that acute and chronic c-MET inhibition drives fatty acid oxidation that in turn can be therapeutically targeted for drug combination therapies. Herein, we summarize and comment on some of our key findings related to this study.

Highlights

In the 1920s of the last century biochemist Otto Warburg made the remarkable and astonishing discovery that malignant cells heavily utilize glucose and metabolize it to lactic acid despite the presence of sufficient oxygen [1]
While at the first glance it may appear to be intuitive that cancer cells should facilitate energy production through most efficient means, aerobic glycolysis enables tumor cells to retain carbons and pass them on to biosynthesis of macromolecules, e.g. purines/pyrimidines, amino acids, fatty acids and cholesterol, that are essential for tumor cell survival and proliferation
Glycolysis in tumor cells is tightly regulated by a couple of known transcription factors: c-Myc, N-Myc, Hypoxia-inducible factor 1-alpha (HIF1α) and others through binding to the promoter regions of key glycolytic enzymes and transporters and are facilitators of the Warburg effect

Summary

Introduction

In the 1920s of the last century biochemist Otto Warburg made the remarkable and astonishing discovery that malignant cells heavily utilize glucose and metabolize it to lactic acid despite the presence of sufficient oxygen [1]. Glycolysis in tumor cells is tightly regulated by a couple of known transcription factors: c-Myc, N-Myc, HIF1α and others through binding to the promoter regions of key glycolytic enzymes and transporters and are facilitators of the Warburg effect. Oxidative energy metabolism is suppressed by HIF1α, a transcription factor whose stability and turn over depends on oxygen levels.

Results

Conclusion