Larbouret Christel, Robert Bruno, Navarro-Teulon Isabelle, Thèzenas Simon, Ladjemi Maha-Zohra, Morisseau Sébastien, Campigna Emmanuelle, Bibeau Frédéric, Mach Jean-Pierre, Pèlegrin André, Azria David
Institut National de la Santé et de la Reserche Médicale, EMI 0227, Centre de Recherche en cancérologie de Montpellier, Université Montpellier I, France.
Clin Cancer Res. 2007 Jun 1;13(11):3356-62. doi: 10.1158/1078-0432.CCR-06-2302.
Pancreatic carcinoma is highly resistant to therapy. Epidermal growth factor receptor (EGFR) and HER2 have been reported to be both dysregulated in this cancer. To evaluate the in vivo effect of binding both EGFR and HER2 with two therapeutic humanized monoclonal antibodies (mAb), we treated human pancreatic carcinoma xenografts, expressing high EGFR and low HER2 levels.
Nude mice, bearing xenografts of BxPC-3 or MiaPaCa-2 human pancreatic carcinoma cell lines, were injected twice weekly for 4 weeks with different doses of anti-EGFR (matuzumab) and anti-HER2 (trastuzumab) mAbs either alone or in combination. The effect of the two mAbs, on HER receptor phosphorylation, was also studied in vitro by Western blot analysis.
The combined mAb treatment significantly inhibited tumor progression of the BxPC-3 xenografts compared with single mAb injection (P = 0.006) or no treatment (P = 0.0004) and specifically induced some complete remissions. The two mAbs had more antitumor effect than 4-fold greater doses of each mAb. The significant synergistic effect of the two mAbs was confirmed on the MiaPaCa-2 xenograft and on another type of carcinoma, SK-OV-3 ovarian carcinoma xenografts. In vitro, the cooperative effect of the two mAbs was associated with a decrease in EGFR and HER2 receptor phosphorylation.
Anti-HER2 mAb has a synergistic therapeutic effect when combined with an anti-EGFR mAb on pancreatic carcinomas with low HER2 expression. These observations may open the way to the use of these two mAbs in a large panel of carcinomas expressing different levels of the two HER receptors.
胰腺癌对治疗具有高度抗性。据报道，表皮生长因子受体（EGFR）和HER2在这种癌症中均存在失调。为了评估两种治疗性人源化单克隆抗体（mAb）结合EGFR和HER2的体内效果，我们对高表达EGFR和低表达HER2的人胰腺癌异种移植瘤进行了治疗。
携带BxPC-3或MiaPaCa-2人胰腺癌细胞系异种移植瘤的裸鼠，每周两次注射不同剂量的抗EGFR（美妥昔单抗）和抗HER2（曲妥珠单抗）单克隆抗体，单独或联合使用，持续4周。还通过蛋白质印迹分析在体外研究了这两种单克隆抗体对HER受体磷酸化的影响。
与单克隆抗体注射（P = 0.006）或不治疗（P = 0.0004）相比，联合单克隆抗体治疗显著抑制了BxPC-3异种移植瘤的肿瘤进展，并特异性地诱导了一些完全缓解。这两种单克隆抗体的抗肿瘤作用比每种单克隆抗体剂量增加4倍以上时更强。在MiaPaCa-2异种移植瘤和另一种癌症SK-OV-3卵巢癌异种移植瘤上证实了这两种单克隆抗体具有显著的协同作用。在体外，这两种单克隆抗体的协同作用与EGFR和HER2受体磷酸化的降低有关。
抗HER2单克隆抗体与抗EGFR单克隆抗体联合使用时，对HER2表达低的胰腺癌具有协同治疗作用。这些观察结果可能为在大量表达不同水平两种HER受体的癌症中使用这两种单克隆抗体开辟道路。
