ErbB receptors: from oncogenes to targeted cancer therapies

Abstract

Understanding the genetic origin of cancer at the molecular level has facilitated the development of novel targeted therapies. Aberrant activation of the ErbB family of receptors is implicated in many human cancers and is already the target of several anticancer therapeutics. The use of mAbs specific for the extracellular domain of ErbB receptors was the first implementation of rational targeted therapy. The cytoplasmic tyrosine kinase domain is also a preferred target for small compounds that inhibit the kinase activity of these receptors. However, current therapy has not yet been optimized, allowing for opportunities for optimization of the next generation of targeted therapy, particularly with regards to inhibiting heteromeric ErbB family receptor complexes.

Figure 1. ErbB receptors and their ligands.

All four members of the ErbB receptor family share high homology in the extracellular domain and the kinase domain. However, ErbB3 is not kinase active. So far no ligand has been found for p185^her2/neu, which has been found to be the preferred dimerization partner for other receptors. Only a few examples of receptor dimers are shown here. Ectodomain-truncated receptors also exist in some cancer cells. NRG1, neuregulin 1.

Figure 2. Molecules in the ErbB signaling pathways as targets for cancer therapies.

FDA-approved drugs include three mAbs targeting the extracellular domain of ErbB and three TKIs targeting the kinase domains. Trastuzumab targets p185^her2/neu. Cetuximab and panitumumab target EGFR. Some TKIs (gefitinib, erlotinib) are only specific for EGFR, while lapatinib and HKI-272 also broadly inhibit other receptors in the family. Inhibitors to molecules downstream of ErbB signaling pathways, such as Src, AKT, survivin, and mTor, are also potential therapeutics for ErbB-mediated transformation. AHNP-SA, AHNP-streptavidin; scFv, single-chain variable fragment.