Dactolisib outperforms Rapamycin in potentiating apoptosis induced by XPO1, Bcl-2 and Mcl-1 blockade in preclinical glioblastoma models.
9 affiliations
- 1Department of Hematology, Oncology & Immunology, Philipps-University Marburg, UKGM Marburg, Germany.
- 2Department of Neurosurgery, Philipps-University Marburg, UKGM Marburg, Germany.
- 3FACS Core Facility, Philipps-University Marburg, Germany.
- 4Department of Neuropathology, Philipps-University Marburg, UKGM Marburg, Germany.
- 5Core Facility Mouse Pathology and Electron Microscopy, Philipps-University Marburg, Germany.
- 6University Cancer Center (UCT) Frankfurt-Marburg, Germany.
- 7Dr. Senckenberg Institute of Neurooncology, Goethe-University Frankfurt, Germany.
- 8Department of Diagnostic and Interventional Radiology, Philipps-University Marburg, UKGM Marburg, Germany.
- 9Department of Nuclear Medicine, Philipps-University Marburg, UKGM Marburg, Germany.
Abstract
Glioblastoma resists therapy through interconnected survival programs. Combined XPO1, Bcl-2, and Mcl-1 inhibition (Eltanexor, Venetoclax, A1210477; EVA) enhances the efficacy of chemotherapy, yet resistance persists. We hypothesized that PI3K/AKT/mTOR (PAM) signaling drives adaptive escape. TCGA/GTEx analyses and immunohistochemistry indicated PAM pathway activation in glioblastoma, with AKT significantly overexpressed, whereas PIK3CA showed a clear trend towards higher expression, although it did not reach statistical significance. qPCR analysis showed that PAM-component expression was highest in patient-derived glioblastoma stem-like cells (GSCs). In U87, U251, and GSCs, the dual PI3K/mTOR inhibitor Dactolisib combined with EVA and 5-Azacytidine reduced viability and induced apoptosis more effectively than any of the Rapamycin combinations, and the difference in apoptosis was most pronounced in U87 and GSCs. Dactolisib monotherapy shifted the cell cycle towards G1 with a reduced S-phase fraction. In CAM xenografts, [¹⁸F]FDG-PET/CT showed decreased tracer uptake, and Caspase-3 activation with PARP cleavage was detected only under EVA + Dactolisib treatment. Taken together, our results suggest that dual PI3K/mTOR inhibition with Dactolisib disables a critical adaptive survival axis, warranting further preclinical evaluation.
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BibTeX
@article{zhao2026dactolisib,
title = {{Dactolisib outperforms Rapamycin in potentiating apoptosis induced by XPO1, Bcl-2 and Mcl-1 blockade in preclinical glioblastoma models.}},
author = {Kai Zhao and Leonie Meyer and Madita Braun and Katharina Otte and Celine Bitter and Maite Pawlik and Hartmann Raifer and Frederik Helmprobst and Axel Pagenstecher and Hans Urban and Michael C Burger and Michael W Ronellenfitsch and Joachim P Steinbach and Jarmila Jedelská and Shamim Bagheri and Behrooz H Yousefi and Pietro Di Fazio and Markus Luster and Andreas H Mahnken and Andreas Neubauer and Andreas Burchert and Christopher Nimsky and Jörg W Bartsch and Tillmann Rusch},
journal = {FEBS open bio},
year = {2026},
month = oct,
doi = {10.1002/2211-5463.70357},
url = {https://europepmc.org/article/MED/42920362},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dactolisib outperforms Rapamycin in potentiating apoptosis induced by XPO1, Bcl-2 and Mcl-1 blockade in preclinical glioblastoma models.
AU - Kai Zhao
AU - Leonie Meyer
AU - Madita Braun
AU - Katharina Otte
AU - Celine Bitter
AU - Maite Pawlik
AU - Hartmann Raifer
AU - Frederik Helmprobst
AU - Axel Pagenstecher
AU - Hans Urban
AU - Michael C Burger
AU - Michael W Ronellenfitsch
AU - Joachim P Steinbach
AU - Jarmila Jedelská
AU - Shamim Bagheri
AU - Behrooz H Yousefi
AU - Pietro Di Fazio
AU - Markus Luster
AU - Andreas H Mahnken
AU - Andreas Neubauer
AU - Andreas Burchert
AU - Christopher Nimsky
AU - Jörg W Bartsch
AU - Tillmann Rusch
PY - 2026
DA - 2026/10/24
JO - FEBS open bio
DO - 10.1002/2211-5463.70357
UR - https://europepmc.org/article/MED/42920362
AB - Glioblastoma resists therapy through interconnected survival programs. Combined XPO1, Bcl-2, and Mcl-1 inhibition (Eltanexor, Venetoclax, A1210477; EVA) enhances the efficacy of chemotherapy, yet resistance persists. We hypothesized that PI3K/AKT/mTOR (PAM) signaling drives adaptive escape. TCGA/GTEx analyses and immunohistochemistry indicated PAM pathway activation in glioblastoma, with AKT significantly overexpressed, whereas PIK3CA showed a clear trend towards higher expression, although it did not reach statistical significance. qPCR analysis showed that PAM-component expression was highest in patient-derived glioblastoma stem-like cells (GSCs). In U87, U251, and GSCs, the dual PI3K/mTOR inhibitor Dactolisib combined with EVA and 5-Azacytidine reduced viability and induced apoptosis more effectively than any of the Rapamycin combinations, and the difference in apoptosis was most pronounced in U87 and GSCs. Dactolisib monotherapy shifted the cell cycle towards G1 with a reduced S-phase fraction. In CAM xenografts, [¹⁸F]FDG-PET/CT showed decreased tracer uptake, and Caspase-3 activation with PARP cleavage was detected only under EVA + Dactolisib treatment. Taken together, our results suggest that dual PI3K/mTOR inhibition with Dactolisib disables a critical adaptive survival axis, warranting further preclinical evaluation.
SN - 2211-5463
ER -