1. Academic Validation
  2. Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models

Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models

  • J Clin Invest. 2020 Feb 3;130(2):699-714. doi: 10.1172/JCI130819.
Lucia Nappi 1 Adeleke H Aguda 1 Nader Al Nakouzi 1 Barbara Lelj-Garolla 1 Eliana Beraldi 1 Nada Lallous 1 Marisa Thi 1 Susan Moore 1 Ladan Fazli 1 Dulguun Battsogt 1 Sophie Stief 1 Fuqiang Ban 1 Nham T Nguyen 2 Neetu Saxena 1 Evgenia Dueva 1 Fan Zhang 1 Takeshi Yamazaki 1 Amina Zoubeidi 1 Artem Cherkasov 1 Gary D Brayer 2 Martin Gleave 1
Affiliations

Affiliations

  • 1 Department of Urologic Sciences, Vancouver Prostate Centre, and.
  • 2 Department of Biochemistry and Molecular Biology, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Abstract

HSP27 is highly expressed in, and supports oncogene addiction of, many cancers. HSP27 phosphorylation is a limiting step for activation of this protein and a target for inhibition, but its highly disordered structure challenges rational structure-guided drug discovery. We performed multistep biochemical, structural, and computational experiments to define a spherical 24-monomer complex composed of 12 HSP27 dimers with a phosphorylation pocket flanked by serine residues between their N-terminal domains. Ivermectin directly binds this pocket to inhibit MAPKAP2-mediated HSP27 phosphorylation and depolymerization, thereby blocking HSP27-regulated survival signaling and client-oncoprotein interactions. Ivermectin potentiated activity of anti-androgen receptor and anti-EGFR drugs in prostate and EGFR/HER2-driven tumor models, respectively, identifying a repurposing approach for cotargeting stress-adaptive responses to overcome resistance to inhibitors of oncogenic pathway signaling.

Keywords

Drug therapy; Oncology.

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