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IL13Rα2‑ and EGFR‑targeted pseudomonas exotoxin potentiates the TRAIL‑mediated death of GBM cells
Nihal Karakaş1, Daniel Stuckey1, Esther Revai-Lechtich1
1Center for Stem Cell Therapeutics and Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
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 α2 (IL13Rα2)‑ 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.
Insights
Targeted toxins sensitize resistant glioblastoma cells to TRAIL therapy by upregulating death receptors. This combination strategy offers new hope for treating difficult brain tumors.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Glioblastomas (GBMs) are aggressive brain tumors with limited treatment options.
- Pro-apoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise but faces resistance in approximately 50% of GBM cells.
- Novel strategies are needed to overcome TRAIL resistance in GBM.
Purpose of the Study:
- To investigate if targeting interleukin-13 receptor alpha2 (IL13Rα2) or epidermal growth factor receptor (EGFR) with Pseudomonas exotoxin (PE) can sensitize TRAIL-resistant GBM cells.
- To assess the combined therapeutic effects of IL13-PE or EGFR nanobody-PE (ENb-PE) with TRAIL on brain tumors.
Main Methods:
- Utilized IL13Rα2- and EGFR-targeted PE toxins to treat TRAIL-resistant GBM and patient-derived GBM stem cells (GSCs).
- Assessed the expression of TRAIL death receptors (DR4, DR5), anti-apoptotic proteins (FLIP, XIAP), and caspase cleavage (caspase-8, caspase-9).
- Evaluated the sensitization of GBM cells to TRAIL-mediated apoptosis.
Main Results:
- Receptor-targeted toxins upregulated TRAIL death receptors (DR4 and DR5).
- Toxins suppressed anti-apoptotic proteins (FLICE-inhibitory protein [FLIP] and X-linked inhibitor of apoptosis protein [XIAP]).
- This led to caspase-8 and caspase-9 cleavage, sensitizing resistant GBM and GSC lines to TRAIL.
Conclusions:
- Targeted toxins enhance TRAIL-mediated apoptosis in resistant GBM cells by modulating death receptor and apoptosis-regulating protein expression.
- This dual-targeting strategy provides a mechanism-based approach for treating a broad spectrum of TRAIL-resistant GBMs.
- Offers potential for cell-mediated delivery of bi-functional therapeutics against challenging brain tumors.
