Abstract 1346: Pan-ERBB inhibitor blocks tumor growth and metastasis

Abstract

Abstract The Epidermal Growth Factor Receptor family of transmembrane tyrosine kinases (ErbB) is over-expressed, correlates with poor prognosis and negatively correlates with disease free survival in many cancer types. EGFR, HER2 and ErbB3 are known to be highly expressed and active, and have been targeted by both kinase inhibitors and monoclonal antibodies, both with disappointing results. Importantly, though, these therapeutics only target either a single receptor or the kinase domain alone. It is well known that these receptors function as heterodimers, and blocking of a single receptor will only promote the hetero-dimerization of the remaining family members. Furthermore, while the tyrosine kinase activity of these receptors is well known, less appreciated are the kinase-independent mechanisms by which they drive cancer progression. These include the modulation of calcium signaling and mitochondrial and nuclear translocation and activity as transcriptional co-factors. The highly conserved juxta-membrane domain (JD) of the ErbB receptors regulates these kinase-independent functions, as well as receptor homo- and hetero-dimerization. Upon ligand binding, the JD forms anti-parallel dimers between the receptors, resulting in receptor dimerization and intracellular trafficking. These protein-protein interactions result in cell growth, survival, migration and invasion. We have previously shown that peptides mimicking this JD can act in a dominant-negative fashion, promoting the formation of non-functional ErbB dimers (consisting of EGFR, HER2 and ErbB3) that induce rapid, ErbB-dependent cell death. Using Cell Penetrating Peptides synthesized in tandem with the JD, these peptides (called EJ1) rapidly cross the plasma membrane, bind the ErbB receptors, and induce cell death in cell lines and PDX lines grown in culture. Death results from a combination of apoptotic and necrotic mechanisms, due to inactivation of mitochondrial function and calcium signaling (as well as kinase inhibition). Although EJ1 peptides display rapid ErbB-dependent cell death in vitro, they are rapidly cleared in vivo, limiting their efficacy. To stabilize in vivo activity, the active peptide (which is an alpha-helix) was stabilized with hydrocarbon staples. Based on this, we hypothesized that SAH-EJ1 would be an effective targeted therapeutic for the treatment of ErbB-dependent cancer. We therefore tested SAH-EJ1 in 3 different ErbB-dependent models of cancer, including EGFRvIII-driven glioblastoma, a PDX model of basal-like breast cancer with EGFR and ErbB3 amplification, and a PDX model of lung cancer with EGFR kinase domain mutations driven by Erlotinib treatment. In each of these models, substantial inhibition of tumor growth was observed, as well as extended survival. Citation Format: Joyce A. Schroeder, Sabrina Maisel, Derrick Broka. Pan-ERBB inhibitor blocks tumor growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1346. doi:10.1158/1538-7445.AM2017-1346