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Orth, M.* ; Albrecht, V.* ; Seidl, K.* ; Kinzel, L.* ; Unger, K. ; Hess J. ; Kreutzer, L. ; Sun, N. ; Stegen, B.* ; Nieto, A.* ; Maas, J.* ; Winssinger, N.* ; Friedl, A.A.* ; Walch, A.K. ; Belka, C. ; Zitzelsberger, H. ; Niyazi, M.* ; Lauber, K.

Inhibition of HSP90 as a strategy to radiosensitize glioblastoma: Targeting the DNA damage response and beyond.

Front. Oncol. 11:612354 (2021)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Radiotherapy is an essential component of multi-modality treatment of glioblastoma (GBM). However, treatment failure and recurrence are frequent and give rise to the dismal prognosis of this aggressive type of primary brain tumor. A high level of inherent treatment resistance is considered to be the major underlying reason, stemming from constantly activated DNA damage response (DDR) mechanisms as a consequence of oncogene overexpression, persistent replicative stress, and other so far unknown reasons. The molecular chaperone heat shock protein 90 (HSP90) plays an important role in the establishment and maintenance of treatment resistance, since it crucially assists the folding and stabilization of various DDR regulators. Accordingly, inhibition of HSP90 represents a multi-target strategy to interfere with DDR function and to sensitize cancer cells to radiotherapy. Using NW457, a pochoxime-based HSP90 inhibitor with favorable brain pharmacokinetic profile, we show here that HSP90 inhibition at low concentrations with per se limited cytotoxicity leads to downregulation of various DNA damage response factors on the protein level, distinct transcriptomic alterations, impaired DNA damage repair, and reduced clonogenic survival in response to ionizing irradiation in glioblastoma cells in vitro. In vivo, HSP90 inhibition by NW457 improved the therapeutic outcome of fractionated CBCT-based irradiation in an orthotopic, syngeneic GBM mouse model, both in terms of tumor progression and survival. Nevertheless, in view of the promising in vitro results the in vivo efficacy was not as strong as expected, although apart from the radiosensitizing effects HSP90 inhibition also reduced irradiation-induced GBM cell migration and tumor invasiveness. Hence, our findings identify the combination of HSP90 inhibition and radiotherapy in principle as a promising strategy for GBM treatment whose performance needs to be further optimized by improved inhibitor substances, better formulations and/or administration routes, and fine-tuned treatment sequences.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Hsp90 Inhibition ; Hsp90i ; Nw457 ; Glioblastoma ; Hypermigration ; Radiosensitization ; Radiotherapy
ISSN (print) / ISBN 2234-943X
e-ISSN 2234-943X
Zeitschrift Frontiers in Oncology
Quellenangaben Band: 11, Heft: , Seiten: , Artikelnummer: 612354 Supplement: ,
Verlag Frontiers
Verlagsort Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) CCG Personalized Radiotherapy in Head and Neck Cancer (KKG-KRT)
Research Unit Radiation Cytogenetics (ZYTO)
Research Unit Analytical Pathology (AAP)
Förderungen FoeFoLe Program of the Medical Faculty of the LMU Munich
Deutsche Forschungsgemeinschaft
Bildungsministerium fuer Bildung und Forschung [German Cancer Consortium (DKTK)]
Bildungsministerium fuer Bildung und Forschung