Ivermectin Inhibits HSP27 and Potentiates Efficacy of Oncogene Targeting in Tumor Models

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2019 Dec 18

PMID 31845908

Citations 31

Authors

Lucia Nappi

Adeleke H Aguda

Nader Al Nakouzi

Barbara Lelj-Garolla

Eliana Beraldi

Nada Lallous

Marisa Thi

Susan Moore

Ladan Fazli

Dulguun Battsogt

Sophie Stief

Fuqiang Ban

Nham T Nguyen

Neetu Saxena

Evgenia Dueva

Fan Zhang

Takeshi Yamazaki

Amina Zoubeidi

Artem Cherkasov

Gary D Brayer

Martin Gleave

Affiliations

Soon will be listed here.

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.

Citing Articles

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O-GlcNAc modification of HSP27 alters its protein interactions and promotes refolding of proteins through the BAG3/HSP70 co-chaperone.

Javed A, Johnson O, Balana A, Volk R, Langen A, Ahn B Protein Sci. 2024; 33(10):e5173.

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