肠癌细胞中KRas基因的频繁突变导致表皮生长因子受体(EGFR)下游信号通路的持续激活，从而减弱或抵消EGFR靶向药Gefitinib的作用效果，造成肠癌细胞对Gefitinib的天然耐药。KRas蛋白具有的结构易变、极易结合GTP等特征给使用传统方法进行KRas抑制剂的开发带来困难。本研究通过噬菌体展示技术筛选出特异结合KRas蛋白的人源性抗体重链可变区(VH)序列，继而将该序列与溶酶体识别片段(CTM)和癌细胞特异结合穿膜肽 (BR2)进行融合表达，构建了BVC (BR2-VH-CTM)系统。BVC能够特异性结合肠癌细胞内野生型和突变型KRas蛋白并促使其进行溶酶体介导的蛋白质降解，从而降低肠癌细胞中KRas的含量，减弱其下游信号通路的激活水平，恢复癌细胞对Gefitinib的敏感性。本研究不仅为靶向药物开发提供了新的策略，也将为肠癌的临床治疗提供重要参考。

Gefitinib suppresses the activation of EGFR and plays an important role in the treatment of multiple cancers, while it shows a little effect in some substypes of colon cancer with EGFR wild type. Studies revealed that the mutation of KRas, a downstream effector of EGFR, could induce the stable activation of Raf-ERK signaling cascades and abrogate the anti-tumor effect of Gefitinib. Therefore, it is urgently needed to suppress the activation of KRas to overcome the Gefitinib resistance in colon cancers. However, KRas is one of the “undruggable proteins” that brings obstacles for designing targeted drugs in traditional methods. In this study, we adopt novel strategy to down regulate the expression of KRas, namely BVC (BR2-VH-CTM). The BVC system contains three parts: the heavy chain variable fragment (VH) antibody against KRas, cancer cell- penetrating peptide (BR2), and the amino acid motif that can be recognized and banded by lysosome (CTM). We have demonstrated that the BVC could selectively entry into colon cancer cells and bind to KRas protein, and finally induce the degradation of KRas in a lysosome dependent manner, thus suppressing the expression of KRas and the activation of the downstream signaling cascades of EGFR, and overcome the Gefitinib resistance in colon cancer cells. Furthermore, the efficiency of BVC in degrading target proteins will be further evaluated, and the combined use of BVC and Gefitinib in prohibiting colon cancer growth will be performed in vitro and in vivo. All in all, our study will provide novel strategy for anti-cancer drug development and colon cancer therapy.