Lack of AKT activation in lung cancer cells with EGFR mutation is a novel marker of cetuximab sensitivity
Lack of AKT activation in lung cancer cells with EGFR mutation is a novel marker of cetuximab sensitivity
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DOI：
10.4161/cbt.19238
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发表时间：
2012-04-01
影响因子：
3.6
通讯作者：
Shimizu, Eiji
中科院分区：
文献类型：
--
作者：
Takata, Miyako;Chikumi, Hiroki;Shimizu, Eiji
表皮生长因子受体（EGFR）突变是EGFR酪氨酸激酶抑制剂吉非替尼敏感性的最佳标志物，但抗EGFR抗体西妥昔单抗的标志物尚未在肺癌中确定。本研究调查了对西妥昔单抗敏感性的标志物。比较肺癌细胞系中EGFR表达、EGFR和KRAS突变以及EGFR基因拷贝数对西妥昔单抗和吉非替尼的敏感性。我们还研究了这些药物对西妥昔单抗敏感和耐药细胞系中EGFR、ERK、AKT和STAT3活化的影响。我们在19个肺癌细胞系中发现了一个EGFR突变的西妥昔单抗敏感细胞系。EGFR下游分子的分析显示，AKT磷酸化在该细胞系中受到抑制。通过转染质粒增强AKT磷酸化诱导西妥昔单抗耐药。西妥昔单抗耐药的获得与该细胞系中的AKT活化相关，而AKT的药理学抑制显著增强西妥昔单抗的生长抑制作用。与EGFR突变相关的AKT去磷酸化是西妥昔单抗敏感性的候选标志物，AKT通路抑制剂与西妥昔单抗联合使用可能是肺癌的新治疗策略。
Epidermal growth factor receptor (EGFR) mutation is the best marker of sensitivity to the EGFR tyrosine kinase inhibitor gefitinib, but a marker for the anti-EGFR antibody cetuximab has not been identified in lung cancer. The present study investigated markers for sensitivity to cetuximab. Sensitivity to cetuximab and gefitinib was compared with EGFR expression, EGFR and KRAS mutation, and EGFR gene copy numbers in lung cancer cell lines. We also studied the effect of these agents on the activation of EGFR, ER K, AKT and STAT3 in cetuximab-sensitive and -resistant cell lines. We found one cetuximab-sensitive cell line with EGFR mutation among 19 lung cancer cell lines. Analysis of molecules downstream from EGFR revealed that AKT phosphorylation was suppressed in this cell line. Augmentation of AKT phosphorylation by transfection of a plasmid induced resistance to cetuximab. Acquisition of cetuximab resistance was associated with AKT activation in this cell line, while pharmacological inhibition of AKT markedly enhanced the growth inhibitory effect of cetuximab. Dephosphorylation of AKT in association with EGFR mutation is a candidate marker for sensitivity to cetuximab, and combined use of an AKT pathway inhibitor with cetuximab could be a novel therapeutic strategy for lung cancer.