Emerging therapies in gastrointestinal cancers

Abstract

Members of the receptor tyrosine kinase family, that include EGFR, ErbB-2/HER-2, ErbB-3/HER-3 and ErbB-4/HER-4, are frequently implicated in experimental models of epithelial cell neoplasia as well as in human cancers. Therefore, interference with the activation of these growth factor receptors represents a promising strategy for development of novel and selective anticancer therapies. Indeed, a number of inhibitors that target either EGFR or HER-2, with the exception of a few that target both; have been developed for treatment of epithelial cancers. Since most solid tumors express different ErbB receptors and/or their ligands, identification of inhibitor(s), targeting multiple EGFR family members may provide a therapeutic benefit to a broader patient population. Here we describe the significance of an ErbB family of receptors in epithelial cancers, and summarize different available therapeutics targeting these receptors. It also emphasizes the need to develop pan-ErbB inhibitors and discusses EGF-Receptor Related Protein, a recently isolated negative regulator of EGFR as a potential pan-ErbB therapeutic for a wide variety of epithelial cancers.

Figure 1

Schematic representation of the four ErbB family members and their respective ligands. The numbers depict percentage homology of each domain relative to EGFR/ErbB-1. There are no known ligands for ErbB-2 and the tyrosine kinase domain is non-functional in ErbB-3, as marked with a cross.

Figure 2

Schematic representations of different ErbBs/EGFRs ligand-induced signaling pathways leading to development and progression of tumors. BTC: betacellulin; EGF: Epidermal growth factor; EGFR: Epidermal growth factor receptor; ERK: Extracellular signal regulated protein kinase; HB-EGF: heparin binding-EGF; Grb: Growth factor receptor receptor binding protein; JNK: c-Jun N-Terminal kinase; MEK: Mitogen activated protein kinase kinase; NDF: neu differentiation factors (also called neuregulins); PI3K: Phosphoinositide-3-kinase; PKB: Protein kinase B; SOS: Son of sevenless;TGF-α: transforming growth factor α.

Figure 3

Different strategies to inhibit EGFRs signaling. mAbs: monoclonal antibodies; siRNA: small interfering ribonucleic acid.

Figure 4

Schematic representation of the comparison of ERRP structure with EGFR (A) and hypothetical mechanism of action of ERRP (B). EGFR: Epidermal growth factor receptor; ERRP: Epidermal growth factor receptor-related protein.