表皮生长因子受体Ⅲ 型突变体（EGFRvⅢ）在乳腺癌的表达对Trastuzumab药物敏感性的影响、机制及对策

Breast cancer is the most common malignant disease affecting women worldwide. Amplification of the human epidermal growth-factor receptor type 2 (HER2) gene occurs in about 20% of human breast cancers and is an independent adverse prognostic marker for disease recurrence and mortality. The anti-HER2 monoclonal antibody, trastuzumab, has been used as firstline therapy for this subset of breast cancers. But, primary and secondary drug resistance remains a haunting issues for trastuzumab. Epidermal Growth Factor Receptor Variant Ⅲ（EGFRvⅢ）,which can only exist in tumor cells, has been detected in the metastasis breast cancer with HER2 positive. EGFRvⅢ has been reported to interact with HER2.Our prelimiliary data indicated that EGFRvⅢ-transfected breast cancer cells had lower sensitivities to Trastuzumab when compared to their parent cells.Therefore, the molecular mechanisms of the contribution of EGFRvIII in trastuzumab resistance will be elucidated in this study. Additionally, the proprietary anti-EGFRvⅢ human-mouse chimeric antibody CH12 (PCT/CN2009/074090) will be combined with trastuzumab to treat the EGFRvIII and Her2 expressing breast cancer cells.This project is expected to provide new therapeutic strategies for treating refractory HER2-positive breast cancer and provide new potential clinical indications for the monoclonal antibody CH12.

乳腺癌是现代女性健康的"头号杀手"，其中20%是HER2 阳性乳腺癌，即"最凶险的乳腺癌"。抗HER2的治疗性单抗Trastuzumab，作为该类乳腺癌患者的基础治疗，已取得显著疗效；但是如何克服治疗过程中出现的原发或继发性耐药，对医学工作者而言仍然是一个巨大挑战。仅在肿瘤细胞中表达的表皮生长因子受体Ⅲ 型突变体（EGFRvⅢ），在部分HER2阳性转移性乳腺癌中也发现有表达，并且与HER2功能关系密切。我们的初步研究发现EGFRvⅢ 阳性的乳腺癌细胞对Trastuzumab的敏感性较低。因此，本研究将进一步探讨其分子机理，并利用自主研制的抗 EGFRvⅢ抗体CH12与Trastuzumab进行联合治疗研究，以期为临床部分难治型的HER2 阳性乳腺癌病人提供新的治疗策略和手段，也为CH12单抗提供新的潜在临床适应症。

乳腺癌是现代女性健康的“头号杀手”，其中20%是HER2 阳性乳腺癌。抗HER2的治疗性单抗Trastuzumab，作为该类乳腺癌患者的基础治疗，已取得显著疗效；但是如何克服治疗过程中出现的原发或继发性耐药，对医学工作者而言仍然是一个巨大挑战。研究发现EGFRvIII通过STAT3途径降低乳腺癌细胞对Trastuzumab治疗敏感性。联合应用抗 EGFRvⅢ抗体CH12和trastuzumab治疗能抑制EGFR下游信号通路从而抑制EGFRvIII+HER2+ 乳腺癌细胞体内、外生长，并且该联合治疗能明显抑制EGFRvIII+HER2+ 乳腺癌细胞血管增生，并促进细胞凋亡。因此，为临床部分难治型的HER2 阳性乳腺癌病人提供新的治疗策略和手段，也为CH12单抗提供新的潜在临床适应症。