IL13R alpha 2-and EGFR-targeted pseudomonas exotoxin potentiates the TRAIL-mediated death of GBM cells

Glioblastomas (GBMs) are refractory to current treatments and novel therapeutic approaches need to be explored. Pro-apoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is tumor-specific and has been shown to induce apoptosis and subsequently kill GBM cells. However, approximately 50% of GBM cells are resistant to TRAIL and a combination of TRAIL with other therapeutics is necessary to induce mechanism-based cell death in TRAIL-resistant GBMs. The present study examined the ability of the tumor cell surface receptor, interleukin (IL)-13 receptor alpha 2 (IL13R alpha 2)- and epidermal growth factor receptor (EGFR)-targeted pseudomonas exotoxin (PE) to sensitize TRAIL-resistant GBM cells and assessed the dual effects of interleukin 13-PE (IL13-PE) or EGFR nanobody-PE (ENb-PE) and TRAIL for the treatment of a broad range of brain tumors with a distinct TRAIL therapeutic response. Receptor targeted toxins upregulated TRAIL death receptors (DR4 and DR5) and suppressed the expression of anti-apoptotic FLICE-inhibitory protein (FLIP) and X-linked inhibitor of apoptosis protein (XIAP). This also led to the induction of the cleavage of caspase-8 and caspase-9 and resulted in the sensitization of highly resistant established GBM and patient-derived GBM stem cell (GSC) lines to TRAIL-mediated apoptosis. These findings provide a mechanism-based strategy that may provide options for the cell-mediated delivery of bi-functional therapeutics to target a wide spectrum of TRAIL-resistant GBMs.