Spreading of EGF Receptor Activity into EGF-free Regions and Molecular Therapies of Cancer

TL;DR

This paper presents a theoretical model explaining how EGFR activity spreads into ligand-free regions, linking this process to cancer pathology and informing molecular therapy design.

Contribution

It introduces a bistable reaction model that accounts for receptor activity spreading without new kinetic parameters, aligning with experimental data.

Findings

Fast initial spreading modes match experiments

Slow propagating fronts are not observed experimentally

Lateral spreading relates to persistent receptor activity in cancer

Abstract

The primary activation of the epidermal growth factor receptor (EGFR) has become a prominent target for molecular therapies against several forms of cancer. But despite considerable progress during the last years, many of its aspects remain poorly understood. Experiments on lateral spreading of receptor activity into ligand-free regions challenge the current standard models of EGFR activation. Here, we propose and study a theoretical model, which explains spreading into ligand-free regions without introducing any new, unknown kinetic parameters. The model exhibits bistability of activity, induced by a generic reaction mechanism, which consists of activation via dimerization and deactivation via a Michaelis-Menten reaction. It possesses slow propagating front solutions and faster initial transients. We analyze relevant experiments and find that they are in quantitative accordance with the fast initial modes of spreading, but not with the slow propagating front. We point out that lateral spreading of activity is linked to pathological levels of persistent receptor activity as observed in cancer cells and exemplify uses of this link for the design and quick evaluation of molecular therapies targeting primary activation of EGFR.