The HSP90 inhibitor Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy: an in vitro and in vivo approach

Sci Rep. 2020 Apr 3;10(1):5923. doi: 10.1038/s41598-020-62293-4.


Oncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy. The HSP90 inhibitor Onalespib initiates the degradation of oncoproteins, and might also act as a radiosensitizer. The aim of this study was therefore to evaluate the efficacy of Onalespib in combination with external beam radiotherapy in an in vitro and in vivo approach. Onalespib downregulated client proteins, lead to increased apoptosis and caused DNA-double-strands. Monotherapy and combination with radiotherapy reduced colony formation, proliferation and migration assessed in radiosensitive HCT116 and radioresistant A431 cells. In vivo, a minimal treatment regimen for 3 consecutive days of Onalespib (3 × 10 mg/kg) doubled survival, whereas Onalespib with radiotherapy (3 × 2 Gy) caused a substantial delay in tumor growth and prolonged the survival by a factor of 3 compared to the HCT116 xenografted control group. Our results demonstrate that Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy, most prominent in the radiosensitive cell models. We speculate that the depletion and downregulation of client proteins involved in signalling, migration and DNA repair mechanisms is the cause. Thus, individually, or in combination with radiotherapy Onalespib inhibits tumor growth and has the potential to improve radiotherapy outcomes, prolonging the overall survival of cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use
  • Cell Movement / drug effects
  • Cell Movement / radiation effects
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Chemoradiotherapy / methods*
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Breaks, Double-Stranded / radiation effects
  • DNA Repair / drug effects
  • Down-Regulation / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • HCT116 Cells
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Isoindoles / pharmacology*
  • Isoindoles / therapeutic use
  • Mice
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Radiation Tolerance / drug effects
  • Xenograft Model Antitumor Assays


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