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Download fileInhibiting Epidermal Growth Factor Receptor Dimerization and Signaling Through Targeted Delivery of a Juxtamembrane Domain Peptide Mimic
journal contribution
posted on 2018-08-22, 00:00 authored by Janessa Gerhart, Anastasia F. Thévenin, Elizabeth Bloch, Kelly E. King, Damien ThéveninOverexpression
and deregulation of the epidermal growth factor
receptor (EGFR) are implicated in multiple human cancers and therefore
are a focus for the development of therapeutics. Current strategies
aimed at inhibiting EGFR activity include monoclonal antibodies and
tyrosine kinase inhibitors. However, activating mutations severely
limit the efficacy of these therapeutics. There is thus a growing
need for novel methods to inhibit EGFR. One promising approach involves
blocking the association of the cytoplasmic juxtamembrane (JM) domain
of EGFR, which has been shown to be essential for receptor dimerization
and kinase function. Here, we aim to improve the selectivity and efficacy
of an EGFR JM peptide mimic by utilizing the pH(low) insertion peptide
(pHLIP), a unique molecule that can selectively target cancer cells
solely based on their extracellular acidity. This delivery strategy
potentially allows for more selective targeting to tumors than current
methods and for anchoring the peptide mimic to the cytoplasmic leaflet
of the plasma membrane, increasing its local concentration and thus
efficacy. We show that the conjugated construct is capable of inhibiting
EGFR phosphorylation and downstream signaling and of inducing concentration-
and pH-dependent toxicity in cervical cancer cells. We envision that
this approach could be expanded to the modulation of other single-span
membrane receptors whose activity is mediated by JM domains.