ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
Disruption of DNA Repair and Survival Pathways through Heat Shock Protein Inhibition by Onalespib to Sensitize Malignant Gliomas to Chemoradiation Therapy.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 23 citations in OpenAlex.
- Glioblastoma research on zebrafish xenograft models: a systematic review.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2024Pooled it
- Antitumor activity and structure-activity relationship of poly (ADP-ribose) polymerase (PARP)-based dual inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Single-nucleus profiling of postmortem diffuse midline gliomas identifies mitochondrial biogenesis as a resistance mechanism to imipridone therapy.Neuro-oncology · 2026Article
- Molecular insights into DNA damage response plasticity in glioma stem cells.Communications biology · 2026Review
- Advances in the Prevention and Treatment of Radiation Skin Injury: Mechanisms, Pharmacological Interventions, and Applications of Novel Dressings.International journal of nanomedicine · 2026Review
- Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights.Acta neuropathologica communications · 2025Review
- Recent advances in the mechanisms of PD-L1 expression in gastric cancer: a review.Biological research · 2025Review
- Potential of ex vivo organotypic slice cultures in neuro-oncology.Neuro-oncology · 2025Review
- Enhancing glioblastoma therapy: unveiling synergistic anticancer effects of Onalespib - radiotherapy combination therapy.Frontiers in oncology · 2025Article
- Epichaperome Inhibition by PU-H71-Mediated Targeting of HSP90 Sensitizes Glioblastoma Cells to Alkylator-Induced DNA Damage.Cancers · 2024Article
- The tumour microenvironment, treatment resistance and recurrence in glioblastoma.Journal of translational medicine · 2024Review
- A transferrin receptor targeting dual-modal MR/NIR fluorescent imaging probe for glioblastoma diagnosis.Regenerative biomaterials · 2024Article
- Combination therapy with HSP90 inhibitors and piperlongumine promotes ROS-mediated ER stress in colon cancer cells.Cell death discovery · 2023Article
- Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies.Signal transduction and targeted therapy · 2023Review
- Natural Products Targeting Hsp90 for a Concurrent Strategy in Glioblastoma and Neurodegeneration.Metabolites · 2022Review
- Tumor microenvironment in glioblastoma: Current and emerging concepts.Neuro-oncology advancesReview
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
purposeProficient DNA repair by homologous recombination (HR) facilitates resistance to chemoradiation in glioma stem cells (GSC). We evaluated whether compromising HR by targeting HSP90, a molecular chaperone required for the function of key HR proteins, using onalespib, a long-acting, brain-penetrant HSP90 inhibitor, would sensitize high-grade gliomas to chemoradiation in vitro and in vivo. EXPERIMENTAL
designThe ability of onalespib to deplete HR client proteins, impair HR repair capacity, and sensitize glioblastoma (GBM) to chemoradiation was evaluated in vitro in GSCs, and in vivo using zebrafish and mouse intracranial glioma xenograft models. The effects of HSP90 inhibition on the transcriptome and cytoplasmic proteins was assessed in GSCs and in ex vivo organotypic human glioma slice cultures.
resultsTreatment with onalespib depleted CHK1 and RAD51, two key proteins of the HR pathway, and attenuated HR repair, sensitizing GSCs to the combination of radiation and temozolomide (TMZ). HSP90 inhibition reprogrammed the transcriptome of GSCs and broadly altered expression of cytoplasmic proteins including known and novel client proteins relevant to GSCs. The combination of onalespib with radiation and TMZ extended survival in a zebrafish and a mouse xenograft model of GBM compared with the standard of care (radiation and TMZ) or onalespib with radiation.
conclusionsThe results of this study demonstrate that targeting HR by HSP90 inhibition sensitizes GSCs to radiation and chemotherapy and extends survival in zebrafish and mouse intracranial models of GBM. These results provide a preclinical rationale for assessment of HSP90 inhibitors in combination with chemoradiation in patients with GBM.
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Registered trials
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