抗EGFR耐药成为RAS野生型转移性结直肠癌（mCRC）治疗中亟待解决的关键问题。我们前期发现FOXO3a可以促进RAS野生型mCRC对EGFR单抗的耐药。深入研究发现耐药细胞中FOXO3a可结合于lnc-GLUD1P7的启动子；lnc-GLUD1P7调控谷氨酰胺代谢通路重要蛋白GLUD1。因此，本课题拟通过临床标本、PDX动物进一步研究lnc-GLUD1P7在转移性结直肠癌EGFR单抗耐药中的作用；通过荧光素酶报告基因、染色质免疫沉淀、液相色谱-质谱联用等探讨lnc-GLUD1P7参与耐药的分子机制，明确其与FOXO3a、谷氨酰胺代谢通路的关系；并通过临床标本动态检测lnc-GLUD1P7，初步探索其作为抗EGFR耐药的生物标志物的潜在价值。本研究发现并提出“lnc-GLUD1P7介导FOXO3a相关代谢通路参与结直肠癌EGFR单抗耐药”的新机制，为发掘新型的耐药标记物提供科学依据。

Resistance to anti-EGFR has become a big challenge to RAS wide-type metastatic colorectal cancer (mCRC). We previously found that FOXO3a could promote resistance to EGFR antibody in RAS wide-type mCRC. Further research found that the binding site of FOXO3a was existed in the promoter region of lnc-GLUD1P7 in resistant cells; lnc-GLUD1P7 could regulate the important protein GLUD1 of glutamine metabolism pathway. In this study, we will further explore the role of lnc-GLUD1P7 in the resistance to anti-EGFR through tissue specimens and PDX animal model; we will explore the molecular mechanism of lnc-GLUD1P7 involved in the EGFR antibody resistance and clarify its relationship with FOXO3a and glutamine metabolism through luciferase reporter gene, chromatin immunoprecipitation, liquid Chromatograph Mass Spectrometer; and we will explore its potential value as an anti EGFR drug resistance biomarker through the dynamic detection of clinical specimens of lnc-GLUD1P7. So, in this study we propose a new mechanism of lnc-GLUD1P7 mediated FOXO3a related metabolic pathway in EGFR antibody resistance of colorectal cancer, and provide scientific basis for the development of new biomarkers for drug resistance.