Pretreatment with pan-integrin inhibitor GLPG-0187 sensitizes GBM cells to radiation

Glioblastoma multiforme (GBM) is the most common primary CNS tumor in adults. Treatment of GBM involves a combination of radiation, chemotherapy, and surgery. Despite significant advancements in radiotherapy, treatment response in GBM remains limited due to challenges such as radioresistance and tumor recurrence. Multiple biological factors contribute to this resistance, including hypoxia, tumor microenvironment interactions, and DNA damage response and repair mechanisms. Previous studies have highlighted the role of integrins in promoting tumor radio resistance under both normoxic and hypoxic conditions. Based on this, we hypothesized that pretreatment of GBM cells with a pan-integrin inhibitor could enhance radiation sensitivity by blocking integrin-mediated pro-survival signaling before radiation-induced stress. In our study, U251 and SNB19 GBM cell lines were treated with GLPG-0187 24 hours before irradiation under both normoxic and hypoxic conditions. CellTiter-Glo (CTG) assays were performed 48 hours post-irradiation, and the combination effects were analyzed using Combenefit software. Under normoxic conditions, pretreatment with GLPG-0187 increased radiation sensitivity in both cell lines. Under hypoxic conditions, pretreatment still enhanced sensitivity, although the effect was attenuated compared to normoxic conditions. Our ongoing studies are expanding these findings to include additional GBM and diffuse intrinsic pontine glioma (DIPG) cell lines and are exploring the molecular pathways affected by this combination treatment. Overall, our results indicate that pan-integrin inhibition prior to radiotherapy could be a promising strategy to improve treatment outcomes in GBM patients.