DDDR-80. ANGPTL4, CEBPD, and IGFBP3 induce TMZ resistance and impact glioblastoma patient survival rates

Abstract Despite the current standard treatment combining temozolomide (TMZ) and radiotherapy, glioblastoma (GBM) can be aggressive and incurable due to drug resistance. This indicates the importance of a comprehensive therapeutic approach in treating GBM. CEBPD, IGFBP3, and ANGPTL4 have been implicated in a more aggressive cancer phenotype by promoting tumors that evade immune surveillance while creating a pro-tumor microenvironment and accelerating progression. Here, we investigate the implications of these genes and associated pathways in GBM and TMZ resistance. Neurosphere- and monolayer-forming cell samples were cultured from three primary GBM cell lines including HK-336, HK-374, and GS-154. RNA sequencing was performed at the Technology Center for Genomics and Bioinformatics at the University of California, Los Angeles. MTT assay was conducted to assess cell viability after TMZ treatment. Transcriptomic data revealed that CEBPD, IGFBP3, and ANGPTL4 are significantly upregulated in the neurosphere-forming stem-cell-like GBM cells across all three cell lines (p < 0.0001). TCGA analysis of healthy brain tissue, compared to diseased GBM tumor, showed significant upregulation of CEBPD (p< 0.01) and IGFBP3 (p < 0.001) in diseased tumors, while no significant change in expression was seen in ANGPTL4 (p=0.36). Moreover, GBM patients with upregulated CEBPD had significantly worse progression-free survival (p < 0.001). Similarly, GBM patients with upregulated IGFBP3 and ANGPTL4 demonstrated significantly worse overall survival (p < 0.0001) and (p < 0.001), respectively. When the two different condition primary cells were treated with TMZ, the neurosphere-forming HK-336, HK-374, and GS-154 cells were significantly more resistant to TMZ treatment than the monolayer-forming cells (p < 0.001). This study highlights the importance of a mechanistic and comprehensive multiple pathways targeted therapeutic approach in treating GBM. Understanding the underlying mechanisms driving these genes and aberrant cellular pathways could provide valuable insights for developing effective combination drug therapies against GBM.