Disruption of DNA Repair and Survival Pathways through Heat Shock Protein Inhibition by Onalespib to Sensitize Malignant Gliomas to Chemoradiation Therapy.

Abstract

PURPOSE:

Proficient 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 DESIGN:

The 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.

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 zebrafish and a mouse xenograft model of GBM compared with 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 patients with GBM.

• Authors: Jihong Xu, Pei-Jung Wu, Tzung-Huei Lai, Pratibha Sharma, Alessandro Canella, Alessandra M Welker, Christine E Beattie, J Brad Elder, Michelle Easley, Russell Lonser, Naduparambil K Jacob, Maciej Pietrzak, Cynthia M Timmers, Frederick Lang, Deepa Sampath, Vinay K Puduvalli
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 9 Pg. 1979-1990 (05 02 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35140124 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Benzamides
• HSP90 Heat-Shock Proteins
• Heat-Shock Proteins
• Isoindoles
• (2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone
• Temozolomide

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides
• Brain Neoplasms (drug therapy, genetics)
• Cell Line, Tumor
• DNA Repair
• Glioblastoma (drug therapy, genetics, radiotherapy)
• Glioma (drug therapy, genetics, radiotherapy)
• HSP90 Heat-Shock Proteins (genetics, metabolism)
• Heat-Shock Proteins (metabolism)
• Humans
• Isoindoles
• Mice
• Temozolomide (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays
• Zebrafish