Resistance to the tyrosine kinase inhibitor axitinib is associated with increased glucose metabolism in pancreatic adenocarcinoma

• Published in: Cell death & disease Vol. 5; no. 4; p. e1160
• Main Authors: Hudson, C D, Hagemann, T, Mather, S J, Avril, N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2014; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/67/1059/2326; 631/67/1504/1713; 631/67/2327; Adenocarcinoma - drug therapy; Adenocarcinoma - enzymology; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Antibodies; Axitinib; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Proliferation - drug effects; Cell Shape - drug effects; Cell Survival - drug effects; Clone Cells; Drug Resistance, Neoplasm - drug effects; Enzyme Activation - drug effects; G2 Phase Cell Cycle Checkpoints - drug effects; Glucose - metabolism; Glucose Transporter Type 1 - metabolism; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Imidazoles - pharmacology; Imidazoles - therapeutic use; Immunology; Indazoles - pharmacology; Indazoles - therapeutic use; Life Sciences; Mice; Mitosis - drug effects; Original; original-article; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; pancreatic adenocarcinoma; drug resistance; molecular targeted therapies; receptor tyrosine kinase inhibitor; glycolysis; PI3K/Akt
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.125

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.