MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, UK.
Gut. 2013 Oct;62(10):1415-24. doi: 10.1136/gutjnl-2012-302039. Epub 2012 Jul 6.
The success of personalised therapy depends on identification and inhibition of the oncogene(s) on which that tumour is dependent. We aimed to determine whether a receptor tyrosine kinase (RTK) array could be used to select the most effective therapeutic strategies in molecularly heterogeneous oesophago-gastric adenocarcinomas.
Gene expression profiling from oesophago-gastric tumours (n=75) and preinvasive stages (n=57) identified the active signalling pathways, which was confirmed using immunohistochemistry (n=434). RTK arrays on a cell line panel (n=14) determined therapeutic targets for in vitro cytotoxic testing. Feasibility of this personalised approach was tested in tumour samples (n=46).
MAPK was the most frequently activated pathway (32/75 samples (42.7%)) with progressive enrichment in preinvasive disease stages (p<0.05) and ERK phosphorylation in 148/434 (34.3%) independent samples. Cell lines displayed a range of RTK activation profiles. When no RTKs were activated, tyrosine kinase inhibitors (TKIs) and a Mek inhibitor were not useful (MKN1). In lines with a dominant phosphorylated RTK (OE19, MKN45 and KATOIII), selection of this TKI or Mek in nM concentrations induced cytotoxicity and inhibited Erk and Akt phosphorylation. In cells lines with complex activation profiles (HSC39 and OE33), a combination of TKIs or Mek inhibition (in nM concentrations) was necessary for cytotoxicity and inhibition of Erk and Akt phosphorylation. Human tumours demonstrated diverse activation profiles and 65% of cases had two or more active RTKs.
The MAPK pathway is commonly activated in oesophago-gastric cancer following activation of a variety of RTKs. Molecular phenotyping can inform a rational choice of targeted therapy.
个体化治疗的成功取决于对肿瘤依赖的致癌基因的识别和抑制。我们旨在确定受体酪氨酸激酶（RTK）阵列是否可用于选择分子异质性食管胃腺癌中最有效的治疗策略。
来自食管胃肿瘤（n=75）和癌前阶段（n=57）的基因表达谱确定了活性信号通路，这通过免疫组织化学（n=434）得到了证实。细胞系面板上的 RTK 阵列（n=14）确定了体外细胞毒性试验的治疗靶点。在肿瘤样本（n=46）中测试了这种个体化方法的可行性。
MAPK 是最常激活的途径（32/75 个样本（42.7%）），在癌前疾病阶段逐渐富集（p<0.05），在 148/434 个（34.3%）独立样本中存在 ERK 磷酸化。细胞系显示出一系列 RTK 激活谱。当没有 RTK 被激活时，酪氨酸激酶抑制剂（TKI）和 Mek 抑制剂没有用（MKN1）。在具有主导磷酸化 RTK（OE19、MKN45 和 KATOIII）的细胞系中，选择该 TKI 或 Mek 在 nM 浓度下诱导细胞毒性并抑制 Erk 和 Akt 磷酸化。在具有复杂激活谱的细胞系（HSC39 和 OE33）中，需要 TKI 或 Mek 抑制（在 nM 浓度下）的组合才能产生细胞毒性并抑制 Erk 和 Akt 磷酸化。人类肿瘤表现出不同的激活谱，65%的病例有两个或更多活跃的 RTK。
MAPK 途径在食管胃腺癌中通常在多种 RTK 激活后被激活。分子表型分析可以为靶向治疗提供合理的选择。
