2. Academic Validation
  3. 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.
PMID: 31845908 DOI: 10.1172/JCI130819
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.

Figures
Products