EGFR单克隆抗体与化疗联用在转移性结直肠癌（metastatic colorectal cancer，mCRC）的治疗上取得重要进展，但EGFR抑制剂的耐药仍是制约其有效性的关键因素，亟需研究其耐药分子机制，为临床治疗提供新的策略。近2年文献调研及项目组前期实验研究均提示Foxo3a在肿瘤发生发展中具有双向调节作用，且作为EGFR下游关键的效应分子参与肿瘤抗EGFR治疗的耐药。前期研究还发现Foxo3a受SP1的调控促进结直肠癌细胞株抵抗凋亡。基于以上结果，我们提出“SP1转录调控FOXO3a，通过激活NF-B参与mCRC中EGFR单克隆抗体耐药”假说。本项目拟从基础生物学结合动物模型及患者肿瘤组织出发多层次深入研究Foxo3a在EGFR单抗耐药中的地位及耐药发生机制。这些研究对阐明转移性结直肠癌中EGFR单克隆抗体耐药的分子机理及进一步优化治疗策略至关重要。

In recent years, the combination of EGFR monoclonal antibody with chemotherapy in treating metastatic colorectal cancer (mCRC) has gained great progress. However the resistance of EGFR monoclonal antibody as the key constraint on the effectiveness is chilling. The molecular mechanism of resistance needs to be studied and will provide a new strategy for clinical treatment. Thus, the mechanism of resistance and the driver factor are still unclear. Nearly two years of literature research and our preliminary experiment pointed out that Foxo3a had two-way regulating functions in the genesis and development of tumor. Foxo3a, a downstream molecular of EGFR, involved in drug resistance and was regulated by SP1.Based on the above results, we proposed the hypothesis that transcriptional regulation of SP1 and Foxo3a will activate NF-KB which participated in the resistance of EGFR monoclonal antibody in mCRC. We will further explore the interacting mechanism of Foxo3a and SP1 in the resistance of EGFR monoclonal antibody by the multiple ways, such as basic biology and animal model. The expecting results will clarify the molecular mechanism of resistance, and search the new strategy of more individualized therapy.