Identification of Hub Genes and Key Pathways Associated with Anti-VEGF Resistant Glioblastoma Using Gene Expression Data Analysis

Abstract

Anti-VEGF therapy is considered to be a useful therapeutic approach in many tumors, but the low efficacy and drug resistance limit its therapeutic potential and promote tumor growth through alternative mechanisms. We reanalyzed the gene expression data of xenografts of tumors of bevacizumab-resistant glioblastoma multiforme (GBM) patients, using bioinformatics tools, to understand the molecular mechanisms of this resistance. An analysis of the gene set data from three generations of xenografts, identified as 646, 873 and 1220, differentially expressed genes (DEGs) in the first, fourth and ninth generations, respectively, of the anti-VEGF-resistant GBM cells. Gene Ontology (GO) and pathway enrichment analyses demonstrated that the DEGs were significantly enriched in biological processes such as angiogenesis, cell proliferation, cell migration, and apoptosis. The protein–protein interaction network and module analysis revealed 21 hub genes, which were enriched in cancer pathways, the cell cycle, the HIF1 signaling pathway, and microRNAs in cancer. The VEGF pathway analysis revealed nine upregulated (IL6, EGFR, VEGFA, SRC, CXCL8, PTGS2, IDH1, APP, and SQSTM1) and five downregulated hub genes (POLR2H, RPS3, UBA52, CCNB1, and UBE2C) linked with several of the VEGF signaling pathway components. The survival analysis showed that three upregulated hub genes (CXCL8, VEGFA, and IDH1) were associated with poor survival. The results predict that these hub genes associated with the GBM resistance to bevacizumab may be potential therapeutic targets or can be biomarkers of the anti-VEGF resistance of GBM.

Real‐time longitudinal analysis of human gliomas reveals in vivo genome evolution and therapeutic impact under standardized treatment

“…Arya et al have shown that by analysing the gene expression data of xenografts of tumours of glioblastoma patients, the resistance mechanism involved PI3K-Akt, cell cycle, and other related signalling pathways. 6 We obtained similar results using real in vivo genomic data in TISF, suggesting this could be a potential mechanism of treatment and resistance associated with bevacizumab treatment.…”

Multi-Omics Binary Integration via Lasso Ensembles (MOBILE) for identification of context-specific networks and new regulatory mechanisms

“…3b). Some were (i) shown to be part of prognostic markers (SLC12A4-CHEK2 (77)), (ii) differentially expressed together in response to perturbations (SEMA3C-TCEAL1 (78), IGFBP2-SIX1 (79), TINCR-POU2AF1 (80), NTSR1-TOMM6 (81)), and (iii) part of gene signatures for different classes of tumors (SNORA73A-MAPK (82), FDCSP-GJA1 (83)). A few of the associations had related mechanistic interactions as well (CDC42-MTOR (84,85), IGFBP2-SIX1 (79), WTAP-STAT3 (86,87), TINCR-POU2AF1 (80)).…”

Novel targets to overcome antiangiogenesis therapy resistance in glioblastoma multiforme: Systems biology approach and suggestion of therapy by galunisertib

“…A study by Zhu et al (2020) demonstrated that AKT suppression could disrupt VM formation and angiogenesis in glioma orthotopic xenografts and glioma cells (Zhu et al, 2020). Kesavan et al (2021) used pathway enrichment analysis to show that 16 genes in the Akt pathway were upregulated, suggesting the pathway is activated in GBM and possibly responsible for the formation of resistance to anti‐VEGF therapy in GBM (Arya et al, 2021).…”

“…(2021) used pathway enrichment analysis to show that 16 genes in the Akt pathway were upregulated, suggesting the pathway is activated in GBM and possibly responsible for the formation of resistance to anti-VEGF therapy in GBM (Arya et al, 2021).…”