Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors.
Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors.
复制标题
表皮生长因子受体和K-RAS突变以及肺癌对胰岛素样生长因子1受体酪氨酸激酶抑制剂的耐药性。
作者：
Kim WY;Prudkin L;Feng L;Kim ES;Hennessy B;Lee JS;Lee JJ;Glisson B;Lippman SM;Wistuba II;Hong WK;Lee HY
大多数非小细胞肺癌（NSCLC）患者对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）的反应较差。我们研究了胰岛素样生长因子1受体（IGF-1 R）信号传导参与EGFR TKI原发性耐药和IGF-1 R TKI耐药的分子决定因素。在NSCLC组织微阵列中对磷酸化IGF-1 R/胰岛素受体（pIGF-1 R/IR）进行了化学发光评价。我们分析了IGF-1 R TKI（PQIP或OSI-906）单独使用或与小分子抑制剂（PD 98059或U 0126）或与靶向K-Ras或MAPK/细胞外信号调节激酶激酶（MEK）的siRNA联合使用在具有不同组织学特征和EGFR或K-Ras突变的NSCLC细胞中的体外和体内抗肿瘤作用。NSCLC标本中的pIGF-1 R/IR表达与吸烟史、鳞状细胞癌组织学、突变型（mut）K-Ras和野生型（wt）EGFR相关，所有这些均与EGFR TKI的不良反应密切相关。IGF-1 R TKI在携带wt EGFR和wt K-Ras的NSCLC细胞中表现出显著的抗肿瘤活性，但在这些基因突变的NSCLC细胞中则没有。mut K-Ras的引入减弱了IGF-1 R TKI对表达wt K-Ras的NSCLC细胞的作用。相反，MEK的失活恢复了携带突变K-Ras的细胞对IGF-TKI的敏感性。EGFR和K-Ras的突变状态可以作为IGF-1 R TKI反应的预测标志物。此外，MEK拮抗作用可消除NSCLC细胞对IGF-1 R TKI的原发性耐药性。
Most patients with non–small cell lung cancer (NSCLC) have responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We investigated the involvement of insulin-like growth factor 1 receptor (IGF-1R) signaling in primary resistance to EGFR TKIs and the molecular determinants of resistance to IGF-1R TKIs. Phosphorylated IGF-1R/insulin receptor (pIGF-1R/IR) was immunohistochemically evaluated in a NSCLC tissue microarray. We analyzed the antitumor effects of an IGF-1R TKI (PQIP or OSI-906), either alone or in combination with a small-molecular inhibitor (PD98059 or U0126) or with siRNA targeting K-Ras or MAPK/extracellular signal-regulated kinase kinase (MEK), in vitro and in vivo in NSCLC cells with variable histologic features and EGFR or K-Ras mutations. pIGF-1R/IR expression in NSCLC specimens was associated with a history of tobacco smoking, squamous cell carcinoma histology, mutant (mut) K-Ras, and wild-type (wt) EGFR, all of which have been strongly associated with poor response to EGFR TKIs. IGF-1R TKIs exhibited significant antitumor activity in NSCLC cells with wt EGFR and wt K-Ras but not in those with mutations in these genes. Introduction of mut K-Ras attenuated the effects of IGF-1R TKIs on NSCLC cells expressing wt K-Ras. Conversely, inactivation of MEK restored sensitivity to IGF-TKIs in cells carrying mut K-Ras. The mutation status of both EGFR and K-Ras could be predictive markers of response to IGF-1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC cells to IGF-1R TKIs.
登录
查看更多内容
影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
DOI：
10.1158/1940-6207.capr-08-0184
发表时间：
2008-12
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Kim WY;Chang DJ;Hennessy B;Kang HJ;Yoo J;Han SH;Kim YS;Park HJ;Seo SY;Mills G;Kim KW;Hong WK;Suh YG;Lee HY
通讯作者：
Lee HY
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
5.7
作者：
Ji, Qun-Sheng;Mulvihill, Mark J.;Pachter, Jonathan A.
通讯作者：
Pachter, Jonathan A.
影响因子：
8.8
作者：
通讯作者：
--