Stapled EGFR peptide reduces inflammatory breast cancer and inhibits additional HER-driven models of cancer

Abstract

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. Electronic supplementary material The online version of this article (10.1186/s12967-019-1939-7) contains supplementary material, which is available to authorized users.

Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR)

“…Later, a stapled peptide was designed to stabilize the conformation and in vivo stability of the helical peptide. The stapled peptide was shown to be more effective in vivo in cancer models to reduce tumor growth [ 90 ]. Furthermore, the substrate binding site of the kinase was also targeted by peptides to EGFR resistant cancer cell lines.…”

Targeting AXL in NSCLC

“…95 Furthermore, analogous to EGFR, stapled peptides against AXL have been a field less explored. 96 , 97 The majority of AXL inhibitors have so far been mostly broad spectrum and displayed off target effects. Further pharmaco-chemical investigations to identify more specific, potent and efficacious AXL inhibitors are of tremendous importance.…”

A novel cyclic NP1 reveals obstruction of EGFR kinase activity and attenuation of EGFR‐driven cell lines

“…Disruptin, a linear peptide, destabilizes the interaction of EGFR and heat shock protein 90 (Hsp90), resulting in receptor degradation 13 . EJ1 elicited dimerization inhibition, leading to the attenuation of downstream signaling 14 . However, in spite of their advantages, peptides are rapidly degraded by peptidases, which are abundant in blood circulation and result in off‐target effects and decreased retention times 15,16 .…”