Hirsch F R, Varella-Garcia M, Cappuzzo F
Department of Medical Oncology, University of Colorado Cancer Center, Aurora, CO 80045, USA.
Oncogene. 2009 Aug;28 Suppl 1:S32-7. doi: 10.1038/onc.2009.199.
Epidermal growth factor receptor (EGFR) and HER2 are cell surface receptor tyrosine kinases (TKs) that transduce growth signals through dimerization with HER family receptors. The heterodimerization of EGFR with HER2 induces a more potent activation of EGFR TK than does EGFR homodimerization. When tumor cells overexpress both EGFR and HER2, they exhibit aggressive tumor cell growth, owing to the increased potential for EGFR/HER2 heterodimerization and signaling. Gefitinib and erlotinib are EGFR TK inhibitors (EGFR TKIs) and have antitumor activity in 8-18% of patients with advanced non-small-cell lung cancer (NSCLC). Certain patient subsets are particularly responsive to EGFR TKIs. Analyses of biomarkers from patients in clinical studies of EGFR TKIs show correlations between objective tumor response and EGFR overexpression, as detected by immunohistochemistry and increased gene copy number measured by fluorescence in situ hybridization analysis. Furthermore, NSCLC tumors that overexpress both EGFR and HER2 are more sensitive to EGFR TKIs than are tumors that overexpress EGFR but are HER2 negative. Therefore, the measurement of EGFR and HER2 protein expression and the gene copy number in NSCLC tumors may have a prognostic value in NSCLC and a predictive value for identifying patients likely to benefit from an EGFR TKI. These considerations suggest that the simultaneous inhibition of EGFR and HER2 may warrant further study in patients with NSCLC.
表皮生长因子受体（EGFR）和HER2是细胞表面受体酪氨酸激酶（TKs），它们通过与HER家族受体二聚化来转导生长信号。EGFR与HER2的异二聚化比EGFR同二聚化诱导更有效的EGFR TK激活。当肿瘤细胞同时过度表达EGFR和HER2时，由于EGFR/HER2异二聚化和信号传导的可能性增加，它们表现出侵袭性的肿瘤细胞生长。吉非替尼和厄洛替尼是EGFR TK抑制剂（EGFR TKIs），在8%-18%的晚期非小细胞肺癌（NSCLC）患者中具有抗肿瘤活性。某些患者亚组对EGFR TKIs特别敏感。对EGFR TKIs临床研究患者的生物标志物分析表明，通过免疫组织化学检测到的客观肿瘤反应与EGFR过表达以及通过荧光原位杂交分析测量的基因拷贝数增加之间存在相关性。此外，同时过度表达EGFR和HER2的NSCLC肿瘤比仅过度表达EGFR但HER2阴性的肿瘤对EGFR TKIs更敏感。因此，测量NSCLC肿瘤中EGFR和HER2蛋白表达及基因拷贝数可能对NSCLC具有预后价值，并对识别可能从EGFR TKI中获益的患者具有预测价值。这些考虑表明，同时抑制EGFR和HER2可能值得在NSCLC患者中进一步研究。
