Patel Dipa, Bassi Rajiv, Hooper Andrea, Prewett Marie, Hicklin Daniel J, Kang Xiaoqiang
ImClone Systems Incorporated, New York, NY, USA.
Int J Oncol. 2009 Jan;34(1):25-32.
Human carcinomas frequently express one or more members of the epidermal growth factor receptor family. Two family members, epidermal growth factor receptor (EGFR) and c-erbB2/neu (HER2), homodimerize or heterodimerize upon activation with ligand and trigger potent mechanisms of cellular proliferation, differentiation and migration. In this study, we examined the effect of the anti-EGFR monoclonal antibody Erbitux (cetuximab) on human tumor cells expressing both EGFR and HER2. Investigation of the effect of cetuximab on the activation of EGFR-EGFR, EGFR-HER2 and HER2-HER2 homodimers and heterodimers was conducted using the NCI-N87 human gastric carcinoma cell line. Treatment of NCI-N87 cells with cetuximab completely inhibited formation of EGFR-EGFR homodimers and EGFR-HER2 heterodimers. Activation of HER2-HER2 homodimers was not appreciably stimulated by exogenous ligand and was not inhibited by cetuximab treatment. Furthermore, cetuximab inhibited EGF-induced EGFR and HER2 phosphorylation in CAL27, NCI-H226 and NCI-N87 cells. The activation of downstream signaling molecules such as AKT, MAPK and STAT-3 were also inhibited by cetuximab in these cells. To examine the effect of cetuximab on the growth of tumors in vivo, athymic mice bearing established NCI-N87 or CAL27 xenografts were treated with cetuximab (1 mg, i.p., q3d). The growth of NCI-N87 and CAL27 tumors was significantly inhibited with cetuximab therapy compared to the control groups (p<0.0001 in both cases). In the CAL27 xenograft model, tumor growth inhibition by cetuximab treatment was similar to that by cetuximab and trastuzumab combination treatment. Immunohistological analysis of cetuximab-treated tumors showed a decrease in EGFR-HER2 signaling and reduced tumor cell proliferation. These results suggest that cetuximab may be useful in the treatment of carcinomas co-expressing EGFR and HER2.
人类癌症常常表达表皮生长因子受体家族的一个或多个成员。该家族的两个成员，即表皮生长因子受体（EGFR）和c-erbB2/neu（HER2），在与配体结合激活后会形成同二聚体或异二聚体，并触发细胞增殖、分化和迁移的有效机制。在本研究中，我们检测了抗EGFR单克隆抗体爱必妥（西妥昔单抗）对同时表达EGFR和HER2的人类肿瘤细胞的影响。使用NCI-N87人胃癌细胞系研究了西妥昔单抗对EGFR-EGFR、EGFR-HER2和HER2-HER2同二聚体及异二聚体激活的影响。用西妥昔单抗处理NCI-N87细胞可完全抑制EGFR-EGFR同二聚体和EGFR-HER2异二聚体的形成。HER2-HER2同二聚体的激活不受外源性配体的明显刺激，且不受西妥昔单抗处理的抑制。此外，西妥昔单抗可抑制CAL27、NCI-H226和NCI-N87细胞中表皮生长因子（EGF）诱导的EGFR和HER2磷酸化。在这些细胞中，西妥昔单抗还可抑制下游信号分子如AKT、丝裂原活化蛋白激酶（MAPK）和信号转导子和转录激活子3（STAT-3）的激活。为检测西妥昔单抗对体内肿瘤生长的影响，对携带已建立的NCI-N87或CAL27异种移植瘤的无胸腺小鼠给予西妥昔单抗（1毫克，腹腔注射，每3天一次）治疗。与对照组相比，西妥昔单抗治疗显著抑制了NCI-N87和CAL27肿瘤的生长（两种情况下p均<0.0001）。在CAL27异种移植瘤模型中，西妥昔单抗治疗对肿瘤生长的抑制作用与西妥昔单抗和曲妥珠单抗联合治疗相似。对经西妥昔单抗处理的肿瘤进行免疫组织学分析显示，EGFR-HER2信号传导减少，肿瘤细胞增殖降低。这些结果表明，西妥昔单抗可能对治疗同时表达EGFR和HER2的癌症有用。
