GLUD1 Promotes Cetuximab Resistance in Metastasis Colorectal Cancer

Abstract

Background: Colorectal cancer (CRC) is one of the most common causes of cancer mortality worldwide, among which metastatic colorectal cancer (mCRC) is the deadliest one. Cetuximab as a monoclonal antibody targeting epidermal growth factor receptor (EGFR) has improved the survival of mCRC patients. However, primary and acquired resistance to cetuximab are often found during therapy. Therefore, it is important to study the mechanism of cetuximab resistance and find more potential biomarkers. Methods: We previously established the acquired cetuximab resistant cell lines Caco2-CR and NCI-H508-CR by treating their parental cetuximab sensitive colorectal cancer cell lines, Caco2 and NCI-H508, with continuously increasing concentrations of cetuximab. Microarray analysis was utilized to detect the expression profiling of resistant cells and sensitive cells. Gene expression data of mCRC treated with cetuximab (GSE5851) was obtained from GEO. Patient-derived xenografts (PDX) were established using the tumor tissues from either primary lesions or liver metastases of mCRC patients without previous treatment. The metabolic flux of 13 C labelled glutamine in NCI-H508-CR and its parental cells was analyzed. Findings: Microarray analysis indicated that GLUD1, a key enzyme in glutamine metabolism, was one of the differentially expressed genes between Caco2-CR and Caco2. The expression of GLUD1 in the cetuximab resistant patients from GSE5851 dataset were higher than that in the sensitive ones. The same results were seen in animal PDX models. The glutamine metabolism was stronger in NCI-H508-CR compared with NCI-H508 and inhibition of glutamine metabolism could reduce the cetuximab resistance. GLUD1 could promote cetuximab resistance by generating more α-KG to support tricarboxylic acid (TCA) cycle. Furthermore, the expression of GLUD1 in resistant cells could be promoted by the nucleus translocated FOXO3. Interpretation: In this study，we found that GLUD1 can promote cetuximab resistance in mCRC, and it was transcriptional regulated by FOXO3. Funding: This work was supported by the National Natural Science Foundation of China (81772511). Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University