Stapled EGFR peptide reduces inflammatory breast cancer and inhibits additional HER-driven models of cancer
AuthorMaisel, Sabrina A
Singh, Shiv K
AffiliationUniv Arizona, Arizona Canc Ctr
Univ Arizona, Dept Mol & Cellular Biol
Inflammatory breast cancer
MetadataShow full item record
CitationMaisel, S. A., Broka, D., Atwell, B., Bunch, T., Kupp, R., Singh, S. K., ... & Schroeder, J. (2019). Stapled EGFR peptide reduces inflammatory breast cancer and inhibits additional HER-driven models of cancer. Journal of Translational Medicine, 17(1), 201.
Rights© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
AbstractBackground: 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.
NoteOpen access journal
VersionFinal published version
SponsorsArizona Cancer Therapeutics; Ginny L Clements Breast Cancer Research Fund; NIH [NIH 1R41CA203353]; NCI [P30 CA023074]
- Combination therapy with anti-ErbB3 monoclonal antibodies and EGFR TKIs potently inhibits non-small cell lung cancer.
- Authors: Noto A, De Vitis C, Roscilli G, Fattore L, Malpicci D, Marra E, Luberto L, D'Andrilli A, Coluccia P, Giovagnoli MR, Normanno N, Ruco L, Aurisicchio L, Mancini R, Ciliberto G
- Issue date: 2013 Aug
- Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers.
- Authors: Roskoski R Jr
- Issue date: 2019 Jan
- Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model.
- Authors: Diaz R, Nguewa PA, Parrondo R, Perez-Stable C, Manrique I, Redrado M, Catena R, Collantes M, Peñuelas I, Díaz-González JA, Calvo A
- Issue date: 2010 May 11
- Afatinib and Temozolomide combination inhibits tumorigenesis by targeting EGFRvIII-cMet signaling in glioblastoma cells.
- Authors: Vengoji R, Macha MA, Nimmakayala RK, Rachagani S, Siddiqui JA, Mallya K, Gorantla S, Jain M, Ponnusamy MP, Batra SK, Shonka N
- Issue date: 2019 Jun 18
- Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models.
- Authors: Cha MY, Lee KO, Kim M, Song JY, Lee KH, Park J, Chae YJ, Kim YH, Suh KH, Lee GS, Park SB, Kim MS
- Issue date: 2012 May 15