Resistance to the tyrosine kinase inhibitor axitinib is associated with increased glucose metabolism in pancreatic adenocarcinoma.
Alterations in energy (glucose) metabolism are key events in the development and progression of cancer. In pancreatic adenocarcinoma (PDAC) cells, we investigated changes in glucose metabolism induced by resistance to the receptor tyrosine kinase inhibitor (RTKI) axitinib. Here, we show that human cell lines and mouse PDAC cell lines obtained from the spontaneous pancreatic cancer mouse model (Kras(G12D)Pdx1-cre) were sensitive to axitinib. The anti-proliferative effect was due to a G2/M block resulting in loss of 70-75% cell viability in the most sensitive PDAC cell line. However, a surviving sub-population showed a 2- to 3-fold increase in [C-14]deoxyglucose ([C-14]DG) uptake. This was sustained in axitinib-resistant cell lines, which were derived from parental PDAC. In addition to the axitinib-induced increase in [C-14]DG uptake, we observed a translocation of glucose transporter-1 (Glut-1) transporters from cytosolic pools to the cell surface membrane and a 2-fold increase in glycolysis rates measured by the extracellular acidification rate (ECAR). We demonstrated an axitinib-induced increase in phosphorylated Protein Kinase B (pAkt) and by blocking pAkt with a phosphatidylinositol-3 kinase (PI3K) inhibitor we reversed the Glut-1 translocation and restored sensitivity to axitinib treatment. Combination treatment with both axitinib and Akt inhibitor in parental pancreatic cell line resulted in a decrease in cell viability beyond that conferred by single therapy alone. Our study shows that PDAC resistance to axitinib results in increased glucose metabolism mediated by activated Akt. Combining axitinib and an Akt inhibitor may improve treatment in PDAC.
1] Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH, USA [2] Centre for Molecular Oncology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Hudson
Centre for Molecular Oncology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Hagemann
Centre for Molecular Oncology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Mather
1] Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH, USA [2] Centre for Molecular Oncology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Avril
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000077784:Axitinib; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D051272:Glucose Transporter Type 1; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D007191:Indazoles; C548887:MK 2206; D047428:Protein Kinase Inhibitors; D000077784:Axitinib; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose