期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 2, 页码 699-714出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI130819
关键词
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资金
- Prostate Cancer Foundation
- Terry Fox New Frontiers Program [1062]
- Prostate Cancer Canada Translation Acceleration Grant
- Canadian Institutes of Health Research [FRN-111082]
- US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- NIH, National Institute of General Medical Sciences (NIGMS) [P41GM103393]
- Michael Smith Foundation for Health Research [16089]
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. lvermectin directly binds this pocket to inhibit MAPKAP2-mediated HSP27 phosphorylation and depolymerization, thereby blocking HSP27-regulated survival signaling and client-oncoprotein interactions. lvermectin 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.
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