Agarwal S, Zerillo C, Kolmakova J, Christensen J G, Harris L N, Rimm D L, Digiovanna M P, Stern D F
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Br J Cancer. 2009 Mar 24;100(6):941-9. doi: 10.1038/sj.bjc.6604937. Epub 2009 Feb 24.
There is a pressing need to identify new drug targets and novel approaches for treatment of non-small-cell lung carcinoma (NSCLC). Members of the epidermal growth factor receptor (EGFR) and Met receptor families have been identified as important molecular targets for NSCLC. Two EGFR tyrosine kinase inhibitors (TKIs; erlotinib and gefitinib) are in current clinical use, but a majority of patients do not respond to these targeted therapies. We used receptor TK (RTK) capture arrays to identify receptors active in NSCLC cell lines. As Met and ErbBs were active, we explored the potential therapeutic advantage of combined targeting of Met with ErbB receptor family inhibitors for treatment of NSCLC. We found that Met physically interacts with both EGFR and Her2 in a NSCLC cell line with overexpression/overactivation of Met. Combined use of a dual EGFR/Her2 inhibitor with a Met inhibitor yields maximal growth inhibition compared with the use of EGFR and/or Met inhibitors. This suggests that simultaneous inhibition of multiple RTKs may be needed to effectively abrogate tumour cell growth. Phosphoproteomic analysis by RTK capture arrays may be a valuable tool for identifying the subset of tumours with functional receptor activation, regardless of mechanism.
迫切需要确定治疗非小细胞肺癌(NSCLC)的新药物靶点和新方法。表皮生长因子受体(EGFR)和Met受体家族成员已被确定为NSCLC的重要分子靶点。两种EGFR酪氨酸激酶抑制剂(TKIs;厄洛替尼和吉非替尼)目前正在临床使用,但大多数患者对这些靶向治疗无反应。我们使用受体TK(RTK)捕获阵列来鉴定在NSCLC细胞系中活跃的受体。由于Met和ErbBs具有活性,我们探索了将Met与ErbB受体家族抑制剂联合靶向治疗NSCLC的潜在治疗优势。我们发现,在一个Met过表达/过度激活的NSCLC细胞系中,Met与EGFR和Her2都存在物理相互作用。与单独使用EGFR和/或Met抑制剂相比,联合使用双靶点EGFR/Her2抑制剂和Met抑制剂可产生最大程度的生长抑制。这表明可能需要同时抑制多个RTK才能有效消除肿瘤细胞生长。通过RTK捕获阵列进行的磷酸化蛋白质组学分析可能是一种有价值的工具,可用于识别具有功能性受体激活的肿瘤亚群,而无需考虑其机制。