Transcriptomic analysis identifies a potential target for bevacizumab resistant glioblastoma

Glioblastoma, IDH wild-type (WHO grade 4) (GBM), is the most common primary brain tumor in adults with a 21-month median overall survival, despite surgical-resection and radio-chemotherapy. Bevacizumab, a monoclonal antibody towards vascular endothelial growth factor-A, is used to treat recurrent-GBM. To find predictors of poor-response, patient-derived xenograft (PDX)-tumors were treated with bevacizumab or vehicle and subsequently grouped based on survival-response; RNAseq expression was then compared by responder-status. Bioinformatic-analysis demonstrated differential gene expression in tumors from poor-responders (six-PDXs) as compared to tumors from good-responders (three-PDXs), along with upregulation of angiogenesis and collagen gene-sets in poor-responders. Within these gene-sets, multiple genes known to be regulated by the early growth response-1 (EGR1) transcription factor, which was also upregulated, were identified and CHRNA7 (α7-nicotinic-acetylcholine receptor, α7-nAChR) was selected for validation. In terms of protein/functional studies, in the bevacizumab-treated poor-responders, nuclear-EGR1 was elevated, Ki67-labeling was increased in EGR1^high tumor, and there was increased angiogenesis. Expression of α7-nAChR and nuclear EGR1 was directly correlated, suggesting CHRNA7 is an EGR1 downstream target. Data-mining (GLASS-database) showed that recurrent GBM in females with an elevated EGR1 and methylated MGMT promoter had a shorter survival. In summary, GBM with increased EGR1 expression, Ki67-labeling in EGR1^high tumor and angiogenesis demonstrated a poor-response to bevacizumab, suggesting EGR1 could be useful in predicting response.