Abstract:
Glioblastoma (GBM), a highly malignant tumour of the central nervous system, presentswith a dire prognosis and low survival rates. The heterogeneous and recurrent nature of GBMrenders current treatments relatively ineffective. In our study, we utilized an integrative systemsbiology approach to uncover the molecular mechanisms driving GBM progression and identify viabletherapeutic drug targets for developing more effective GBM treatment strategies. Our integrativeanalysis revealed an elevated expression of CHST2 in GBM tumours, designating it as an unfavourableprognostic gene in GBM, as supported by data from two independent GBM cohorts. Further, wepinpointed WZ-4002 as a potential drug candidate to modulate CHST2 through computational drugrepositioning. WZ-4002 directly targeted EGFR (ERBB1) and ERBB2, affecting their dimerization andinfluencing the activity of adjacent genes, including CHST2. We validated our findings by treatingU-138 MG cells with WZ-4002, observing a decrease in CHST2 protein levels and a reduction incell viability. In summary, our research suggests that the WZ-4002 drug candidate may effectivelymodulate CHST2 and adjacent genes, offering a promising avenue for developing efficient treatmentstrategies for GBM patients.
Keywords: glioblastoma; survival; co-expression; drug repositioning; glycosaminoglycans;extracellular matrix
