title: Early changes in [18F]FDG incorporation by breast cancer cells treated with trastuzumab in normoxic conditions: role of the Akt-pathway, glucose transport and HIF-1α.
abstract: HER-2 overexpression does not guarantee response to HER2-targeting drugs such as trastuzumab, which is cardiotoxic and expensive, so early detection of response status is crucial. Factors influencing [(18)F]FDG incorporation in the timeframe of cell signalling down-regulation subsequent to trastuzumab treatment are investigated to provide a better understanding of the relationship between growth response and modulation of [(18)F]FDG incorporation. HER-2-overexpressing breast tumour cell lines, MDA-MB-453, SKBr3 and BT474 and MDA-MB-468 (HER2 non-over-expressor) were treated with trastuzumab (4 h) and probed for AKT, pAKT, ERK1/2, pERK1/2 and HIF-1α to determine early signalling pathway inhibitory effects of trastuzumab. Cells incubated with trastuzumab and/or PI3K inhibitor LY294002 and ERK1/2 inhibitor U0126 and glucose transport and [(18)F]FDG incorporation measured. Cell lines expressed AKT, pAKT, ERK1/2 and pERK1/2 but not HIF-1α. Trastuzumab treatment decreased pAkt but not pERK1/2 levels. Trastuzumab did not further inhibit AKT when maximally inhibited with LY294002. Treatment with LY294002 and trastuzumab for 4 h decreased [(18)F]FDG incorporation in BT474 and MDA-MB-453 but not SKBr3 cells. LY294002 inhibited glucose transport by each cell line, but the glucose transport rate was tenfold higher by SKBr3 cells than BT474 and MDA-MB-453 cells. AKT-induced uptake of [(18)F]FDG was found to be HIF-1α independent in breast cancer cell lines. AKT inhibition level and tumour cell glucose transport rate can influence whether or not PI3K inhibitors affect [(18)F]FDG incorporation which may account for the variation in preclinical and clinical findings associated with [(18)F]FDG-PET in response to trastuzumab and other HER-2 targeting drugs.
authors: Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen, AB24 2TN, UK.
authors: Ian N
authors: IN
authors: Fleming
authors: Alexandra
authors: A
authors: Andriu
authors: Tim A D
authors: TA
authors: Smith
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D002867:Chromones; D019788:Fluorodeoxyglucose F18; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C497442:HIF1A protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C508053:ERBB2 protein, human