Date of Award

January 2014

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Marcus Bosenberg

Subject Area(s)

Molecular biology, Cellular biology, Medicine

Abstract

Vemurafenib is the first FDA-approved personalized treatment for metastatic melanoma to show an improvement in survival. This serine threonine kinase inhibitor targets the mutated BRAF V600E protein, which occurs in approximately 50% of melanomas. The downstream effect of BRAF V600E blockade is inhibition of cell proliferation. Little is known about the effect of vemurafenib on glucose metabolism in melanoma cells. The Warburg effect, or the use aerobic glycolysis to generate energy and building blocks for cell proliferation, is a hallmark of cancer. Normal cells, in contrast, metabolize glucose through oxidative phosphorylation in the presence of oxygen and through glycolysis in anaerobic environments. Vemurafenib decreases glucose uptake in sensitive human melanoma cell lines but not in intrinsically resistant lines or lines that have been passaged to become resistant. The Braf/Pten mouse model of melanoma shows no major decrease in glucose uptake with treatment with PLX4720, an analog of vemurafenib, of up to 28 days perhaps because PTEN deletion removes the negative feedback on the PI3K/mTOR pathway of cell metabolism. The decrease in uptake seen in vitro is associated with a decrease in hexokinase (HK) activity, which is required for entrapment of glucose as glucose-6-phosphate inside the cell, but not with significant changes in mRNA levels of glucose transporters or hexokinases (GLUT1, GLUT2, GLUT3, HK1, or HK2). The global effect of vemurafenib on glucose metabolism is decreased flux through glycolysis as shown by decreased lactate levels. These observations indicate vemurafenib targets the deregulated metabolism of human melanoma cells. This finding may lead to the discovery and development of novel therapeutics that specifically target the abnormal metabolism of cancer cells.

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