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.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • A549 Cells
  • Animals
  • Heat-Shock Proteins* / antagonists & inhibitors
  • Heat-Shock Proteins* / chemistry
  • Heat-Shock Proteins* / genetics
  • Heat-Shock Proteins* / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ivermectin* / chemistry
  • Ivermectin* / pharmacology
  • Mice
  • Molecular Chaperones* / antagonists & inhibitors
  • Molecular Chaperones* / chemistry
  • Molecular Chaperones* / genetics
  • Molecular Chaperones* / metabolism
  • Neoplasms, Experimental* / drug therapy
  • Neoplasms, Experimental* / genetics
  • Neoplasms, Experimental* / metabolism
  • Neoplasms, Experimental* / pathology
  • Protein Domains
  • Protein Multimerization
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Receptor, ErbB-2* / genetics
  • Receptor, ErbB-2* / metabolism

Substances

  • HSPB1 protein, human
  • Heat-Shock Proteins
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Ivermectin
  • MAP-kinase-activated kinase 2
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Protein Serine-Threonine Kinases