Disruption of DNA Repair and Survival Pathways through Heat Shock Protein inhibition by Onalespib to Sensitize Malignant Gliomas to Chemoradiation therapy
- Xu, J., Wu, P.J., Lai, T.H., Sharma, P., Canella, A., Welker, A.M., Beattie, C., Timmers, C.D., Lang, F.F., Jacob, N.K., Elder, J.B., Lonser, R., Easley, M., Pietrzak, M., Sampath, D., Puduvalli, V.K.
- Clinical cancer research : an official journal of the American Association for Cancer Research 28(9): 1979-1990 (Journal)
- Registered Authors
- Beattie, Christine
- MeSH Terms
- Antineoplastic Agents*/pharmacology
- Brain Neoplasms*/drug therapy
- Brain Neoplasms*/genetics
- Cell Line, Tumor
- DNA Repair
- Glioblastoma*/drug therapy
- Glioma*/drug therapy
- HSP90 Heat-Shock Proteins/genetics
- HSP90 Heat-Shock Proteins/metabolism
- Heat-Shock Proteins/metabolism
- Temozolomide/therapeutic use
- Xenograft Model Antitumor Assays
- 35140124 Full text @ Clin. Cancer Res.
Xu, J., Wu, P.J., Lai, T.H., Sharma, P., Canella, A., Welker, A.M., Beattie, C., Timmers, C.D., Lang, F.F., Jacob, N.K., Elder, J.B., Lonser, R., Easley, M., Pietrzak, M., Sampath, D., Puduvalli, V.K. (2022) Disruption of DNA Repair and Survival Pathways through Heat Shock Protein inhibition by Onalespib to Sensitize Malignant Gliomas to Chemoradiation therapy. Clinical cancer research : an official journal of the American Association for Cancer Research. 28(9):1979-1990.
Purpose Proficient DNA repair by homologous recombination (HR) facilitates resistance to chemo-radiation in glioma stem cells (GSCs). 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 chemo-radiation in vitro and in vivo Experimental Design: The ability of onalespib to deplete HR client proteins, impair HR repair capacity, and sensitize GBM to chemo-radiation 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.
Results Treatment 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 zebra fish and a mouse xenograft model of GBM compared to the standard of care (radiation and TMZ) or onalespib with radiation.
Conclusions The 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 GBM patients.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes