Are HER1/EGFR interactions with ligand free HER2 related to the effects of HER1-targeted drugs?

Abstract

This paper is aimed to describe consequences of possible dimerization modes between ligand binding HER1 and ligand free HER2 receptors on cellular membrane. Cells without HER2/neu need high exposure to HER1 ligands for growth stimulation since formation of HER1-ligand:HER1-ligand homodimers depends on the number of both HER1 and ligand molecules and an "all or none" threshold under which cell growth is not stimulated can be expected. Cells with HER2/neu molecules on their surface can react to moderate or even low HER1 ligand exposure through formation of HER2:HER1-ligand dimers, making them more sensitive to growth stimulation by EGF or other ligands without the "all or none" threshold in cell growth stimulation. Formation of some HER2:HER2 homodimers can provide the basal cell growth stimulation despite available ligands to HER1. In tumors, high expression of HER2 can lead to many HER2:HER2 homodimers and increased cell growth that contributes to a poor prognosis. Here presented concept is that some 75 millions of years ago, introduction of HER2/neu with increased sensitivity to low EGFR ligand exposure, might be the cause of increased variability of HER1 expression on normal cells and of the basal EGF secretion from the uninjured tissue. Spontaneous formation of HER2:HER2 homodimers in cells with HER2/neu expression might have substituted the low ligand exposure from uninjured tissue and thus slowly reduce importance of basal secretions of EGFR ligands. Reported variability in HER1 tumor expression and response to HER1-targeted agents, a wide range of EGF concentration in healthy women breasts fluid and the skin rash/tumor response relation to HER1-targeted drugs are discussed as possible examples of individual differences in tissue dependency on HER1 interactions with ligands in normal and cancer tissue.