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Stapled EGFR peptide reduces inflammatory breast cancer and inhibits additional HER-driven models of cancer
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Stapled EGFR peptide reduces inflammatory breast cancer and inhibits additional HER-driven models of cancer
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Journal Article
Stapled EGFR peptide reduces inflammatory breast cancer and inhibits additional HER-driven models of cancer
2019
Overview
Background
The human epidermal growth factor receptor (HER) family of transmembrane tyrosine kinases is overexpressed and correlates with poor prognosis and decreased survival in many cancers. The receptor family has been therapeutically targeted, yet tyrosine kinase inhibitors (TKIs) do not inhibit kinase-independent functions and antibody-based targeting does not affect internalized receptors. We have previously demonstrated that a peptide mimicking the internal juxtamembrane domain of HER1 (EGFR; EJ1) promotes the formation of non-functional HER dimers that inhibit kinase-dependent and kinase-independent functions of HER1 (ERBB1/EGFR), HER2 (ERBB2) and HER3 (ERBB3). Despite inducing rapid HER-dependent cell death in vitro, EJ1 peptides are rapidly cleared in vivo, limiting their efficacy.
Method
To stabilize EJ1 activity, hydrocarbon staples (SAH) were added to the active peptide (SAH-EJ1), resulting in a 7.2-fold increase in efficacy and decreased in vivo clearance. Viability assays were performed across HER1 and HER2 expressing cell lines, therapeutic-resistant breast cancer cells, clinically relevant HER1-mutated lung cancer cells, and patient-derived glioblastoma cells, in all cases demonstrating improved efficacy over standard of care pan-HER therapeutics. Tumor burden studies were also performed in lung, glioblastoma, and inflammatory breast cancer mouse models, evaluating tumor growth and overall survival.
Results
When injected into mouse models of basal-like and inflammatory breast cancers, EGFRvIII-driven glioblastoma, and lung adenocarcinoma with Erlotinib resistance, tumor growth is inhibited and overall survival is extended. Studies evaluating the toxicity of SAH-EJ1 also demonstrate a broad therapeutic window.
Conclusions
Taken together, these data indicate that SAH-EJ1 may be an effective therapeutic for HER-driven cancers with the potential to eliminate triple negative inflammatory breast cancer.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ Animals
/ Biomedical and Life Sciences
/ Brain Neoplasms - drug therapy
/ Cell Proliferation - drug effects
/ Down-Regulation - drug effects
/ EGFR
/ EJ1
/ Epidermal growth factor receptors
/ Erb-b2 Receptor Tyrosine Kinases - genetics
/ Female
/ Genomics
/ HER
/ Humans
/ Inflammatory Breast Neoplasms - drug therapy
/ Inflammatory Breast Neoplasms - genetics
/ Inflammatory Breast Neoplasms - pathology
/ Kinases
/ Ligands
/ Lung Neoplasms - drug therapy
/ Mice
/ Mimicry
/ Mutation
/ Peptide Fragments - chemistry
/ Peptide Fragments - therapeutic use
/ Peptides
/ Proteins
/ Toxicity
