Fleming Ian N, Andriu Alexandra, Smith Tim A D
Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen, AB24 2TN, UK.
Breast Cancer Res Treat. 2014 Apr;144(2):241-8. doi: 10.1007/s10549-014-2858-1. Epub 2014 Feb 13.
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.
HER-2过表达并不保证对曲妥珠单抗等HER2靶向药物有反应，而曲妥珠单抗具有心脏毒性且价格昂贵，因此早期检测反应状态至关重要。研究了在曲妥珠单抗治疗后细胞信号下调时间范围内影响[(18)F]FDG摄取的因素，以更好地理解生长反应与[(18)F]FDG摄取调节之间的关系。用曲妥珠单抗（4小时）处理HER-2过表达的乳腺癌细胞系MDA-MB-453、SKBr3和BT474以及MDA-MB-468（HER2非过表达细胞系），并检测AKT、pAKT、ERK1/2、pERK1/2和HIF-1α，以确定曲妥珠单抗对早期信号通路的抑制作用。用曲妥珠单抗和/或PI3K抑制剂LY294002以及ERK1/2抑制剂U0126孵育细胞，测量葡萄糖转运和[(18)F]FDG摄取。细胞系表达AKT、pAKT、ERK1/2和pERK1/2，但不表达HIF-1α。曲妥珠单抗治疗降低了pAkt水平，但未降低pERK1/2水平。当用LY294002最大程度抑制时，曲妥珠单抗未进一步抑制AKT。用LY294002和曲妥珠单抗处理4小时可降低BT474和MDA-MB-453细胞中的[(18)F]FDG摄取，但对SKBr3细胞无影响。LY294002抑制每个细胞系的葡萄糖转运，但SKBr3细胞的葡萄糖转运速率比BT474和MDA-MB-453细胞高10倍。发现在乳腺癌细胞系中，AKT诱导的[(18)F]FDG摄取与HIF-1α无关。AKT抑制水平和肿瘤细胞葡萄糖转运速率可能影响PI3K抑制剂是否影响[(18)F]FDG摄取，这可能解释了与[(18)F]FDG-PET相关临床前和临床研究结果在对曲妥珠单抗和其他HER-2靶向药物反应方面的差异。
