Abstract
Bevacizumab combined with cytotoxic chemotherapy is the backbone of metastatic colorectal cancer (mCRC) therapy; however, its treatment efficacy is hampered by therapeutic resistance. Therefore, understanding the mechanisms underlying bevacizumab resistance is crucial to increasing the therapeutic efficacy of bevacizumab. The Gene Expression Omnibus (GEO) database (dataset, GSE86525) was used to identify the key genes and pathways involved in bevacizumab-resistant mCRC. The GEO2R web tool was used to identify differentially expressed genes (DEGs). Functional and pathway enrichment analyses of the DEGs were performed using the Database for Annotation, Visualization, and Integrated Discovery(DAVID). Protein–protein interaction (PPI) networks were established using the Search Tool for the Retrieval of Interacting Genes/Proteins database(STRING) and visualized using Cytoscape software. A total of 124 DEGs were obtained, 57 of which upregulated and 67 were downregulated. PPI network analysis showed that seven upregulated genes and nine downregulated genes exhibited high PPI degrees. In the functional enrichment, the DEGs were mainly enriched in negative regulation of phosphate metabolic process and positive regulation of cell cycle process gene ontologies (GOs); the enriched pathways were the phosphoinositide 3-kinase-serine/threonine kinase signaling pathway, bladder cancer, and microRNAs in cancer. Cyclin-dependent kinase inhibitor 1A(CDKN1A), toll-like receptor 4 (TLR4), CD19 molecule (CD19), breast cancer 1, early onset (BRCA1), platelet-derived growth factor subunit A (PDGFA), and matrix metallopeptidase 1 (MMP1) were the DEGs involved in the pathways and the PPIs. The clinical validation of the DEGs in mCRC (TNM clinical stages 3 and 4) revealed that high PDGFA expression levels were associated with poor overall survival, whereas high BRCA1 and MMP1 expression levels were associated with favorable progress free survival(PFS). The identified genes and pathways can be potential targets and predictors of therapeutic resistance and prognosis in bevacizumab-treated patients with mCRC.
Highlights
Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer deaths worldwide, accounting for 10% of the worldwide cancer incidence and mortality [1]
The GEO2R tool was used to identify differentially expressed genes (DEGs) from the data derived from the GPL16699 oligonucleotide microarray platform, comprising 62,976 probe sets
A total of 124 DEGs were determined to be associated with bevacizumab resistance, with 57 being upregulated and 67 being downregulated, as determined according to their log2FC and false discovery rate (FDR) values (S1 and S2 Tables)
Summary
Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer deaths worldwide, accounting for 10% of the worldwide cancer incidence and mortality [1]. Bevacizumab is the first agent to influence OS in patients with metastatic CRC (mCRC); when combined with irinotecan-based chemotherapy, the median OS improved from 15.6 to 20.3 months, median PFS from 6.2 to 10.6 months and RR from 34.8% to 44.8%[10]. When compared for effectiveness, the irinotecan based chemotherapy has shown to have an edge over oxaliplatin based chemotherapy with the addition of bevacizumab (OS = 31.4 vs 30.1 months, PFS = 12.1 vs 10.7 months)[15]. These results have been echoed in the MAVERICC trial (OS = 27.5 vs 23.9 months, PFS = 12.6 vs 10.1 months)[16]. The therapeutic effects of bevacizumab are strongly affected by the lack of biomarkers that can facilitate selecting a population that might benefit from this medication and can predict therapeutic resistance [18,19,20]
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