Targeting erbB receptors

Abstract

Our work is concerned with the origins and therapy of human cancers. Members of the epidermal growth factor receptor (EGFR) family of tyrosine kinases, also known as erbB or HER receptors, are over expressed and/or activated in many types of human tumors and represent important therapeutic targets in cancer therapy. Studies from our laboratory identified targeted therapy as a way to treat cancer. Rational therapeutics targeting and disabling erbB receptors have been developed to reverse the malignant properties of tumors. Reversal of the malignant phenotype, best seen with disabling the HER2 receptors using monoclonal antibodies is a distinct process from that seen with blocking of ligand binding to cognate receptors as has been done for EGFr receptors. Here we review the mechanisms of action deduced from a number of approaches developed in our laboratory and elsewhere, including monoclonal antibodies, peptide mimetics, recombinant proteins and small molecules. The biochemical and biological principles which have been uncovered during these studies of disabling HER2 homomeric or HER2-EGFr heteromeric receptors will help the development of novel and more efficient therapeutics targeting erbB family receptors.

Fig. 1

Mechanisms of function of therapeutic agents targeting ectodomains of receptors. Receptor ectodomains were represented by circular disks, in which the dimerization interfaces were colored by gray. (A) Monoclonal antibodies 4D5 and 7.16.4 can promote the formation of functionally defective receptor tetramers; (B) monoclonal antibody chA21 appears to cross-link dimers of the receptors to form large defective receptor complexes which are internalized; (C) peptide mimetics AHNP (antibody mimetic) and S22 (dimerization-blocking peptide) can interfere with receptor dimers; (D) like the parental antibody, ASA may also promote the formation of defective receptor tetramers.

Fig. 2

Three-dimensional structure of AHNP as determined by NMR.

Fig. 3

Representations of T691, a trans inhibitory mutant of p185^her2/neu. Receptor ectodomains were represented by circular disks, in which the dimerization interfaces were colored by gray. Intracellular kinase domains of the receptors were represented by two filled ellipses, and transmembrane domain was represented by lines.