Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond

Article Article scientifique Article Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond eng 2021-03-17 2021-03-17 author Orth Michael 0000-0002-4608-7151 author Albrecht Valerie author Seidl Karin author Kinzel Linda author Unger Kristian 0000-0002-0374-2320 author Hess Julia author Kreutzer Lisa author Sun Na 0000-0003-0155-1763 819230 author Stegen Benjamin author Nieto Alexander author Maas Jessica author Winssinger Nicolas 0000-0003-1636-7766 769664 Département de chimie organique (CHIOR) author Friedl Anna A. author Walch Axel K. author Belka Claus author Zitzelsberger Horst author Niyazi Maximilian 0000-0002-7711-9486 author Lauber Kirsten 612354 10.3389/fonc.2021.612354 33816244 2234-943X PMC8011354 https://www.frontiersin.org/articles/10.3389/fonc.2021.612354/full <p> 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. </p> HSP90 inhibition HSP90i NW457 Glioblastoma Hypermigration Radiosensitization Radiotherapy Dewey 540 Bundesministerium fÃ¼r Bildung und Forschung 02NUK047C, DKTK Medizinischen FakultÃ¤t, Ludwig-Maximilians-UniversitÃ¤t MÃ¼nchen FoeFoLe Deutsche Forschungsgemeinschaft INST 409/126-1 FUGG, INST 409/20-1 FUGG, INST 409/22-1 FUGG 36 Département de chimie organique 141 false 762 Groupe Winssinger Frontiers in oncology 11 8a4486eb-2a72-402c-8178-a142a4cc55f0 Article (Published version) Public Article_scientifique_from_unpaywall.pdf 13479881 application/pdf CC BY e364629d90027cfb26a3e592b32d065cdf36f1bd970809f372081ad5c61ff9ca openAccess Faculté des sciences / Section de chimie et biochimie / Département de chimie organique

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Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond	Frontiers in oncology			2021	88	56

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