Reversion of the ErbB malignant phenotype and the DNA damage response

Abstract

The ErbB or HER family is a group of membrane bound tyrosine kinase receptors that initiate signal transduction cascades, which are critical to a wide range of biological processes. When over-expressed or mutated, members of this kinase family form homomeric or heteromeric kinase assemblies that are involved in certain human malignancies. Targeted therapy evolved from studies showing that monoclonal antibodies to the ectodomain of ErbB2/neu would reverse the malignant phenotype. Unfortunately, tumors develop resistance to targeted therapies even when coupled with genotoxic insults such as radiation. Radiation treatment predominantly induces double strand DNA breaks, which, if not repaired, are potentially lethal to the cell. Some tumors are resistant to radiation treatment because they effectively repair double strand breaks. We and others have shown that even in the presence of ionizing radiation, active ErbB kinase signaling apparently enhances the repair process, such that transformed cells resist genotoxic signal induced cell death. We review here the current understanding of ErbB signaling and DNA double strand break repair. Some studies have identified a mechanism by which DNA damage is coordinated to assemblies of proteins that associate with SUN domain containing proteins. These assemblies represent a new target for therapy of resistant tumor cells.