Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models
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.
- Ivermectin binds phosphorylation pocket of HSP27 to inhibit stress-mediated phopho-activation and depolymerization of HSP27
- IVM also dose-dependently inhibited HSP27 interaction with unfolded insulin [Video where Dr Ken Berry claims high insulin is a main driver to enlarged prostate symptoms.]
- Ivermectin directly binds HSP27 and prevents its interaction with misfolded proteins
- IVM inhibition of HSP27 is synergistically lethal to cells with oncogenic activation of EGFR or AR(androgen receptor)
- Ivermectin inhibits phosphorylation and oligomerization of HSP27 in cancer cells.
- IVM potently inhibited HSP27 phosphorylation in lung and prostate cancer as well as bladder and breast cancer cells.
- The pharmacokinetic profile of IVM was determined to support tumor growth inhibition studies in vivo.
- IVM significantly delayed docetaxel-resistant PC3 tumor progression
- Repurposing IVM in cancer would require higher and longer dosing than its approved use as an antiparasitic.
- While no significant adverse events were observed in the many in vivo experiments in this study, IVM activates GABA-A receptor activity, which can produce neurologic toxicity. To address these issues, IVM analogs have been designed with lower affinity to the GABA-A receptor while maintaining favorable oral bioavailability, pharmacokinetics, and HSP27 binding affinity, from which a lead compound will be selected for clinical development in combination with AR and EGFR/HER2 inhibitors.