Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment

The ErbB receptors and their cognate ligands that belong to the epidermal growth factor (EGF) family of peptides are involved in the pathogenesis of different types of carcinomas. In fact, the ErbB receptors and the EGF-like growth factors are frequently expressed in human tumors. These proteins form a complex system that regulates the proliferation and the survival of cancer cells. Therefore, ErbB receptors and their ligands might represent suitable targets for novel therapeutic approaches in human carcinomas. In this regard, different target-based agents that are directed against the ErbB receptors have been developed in the past two decades. One of these compounds, the humanized anti-ErbB-2 monoclonal antibody trastuzumab has been approved for the treatment of patients with metastatic breast cancer. The anti-EGF receptor (EGFR) antibody C225, as well as EGFR tyrosine kinase inhibitors ZD1839 and OSI-774 are currently in phase III clinical development. Several other ErbB tyrosine kinase inhibitors are in phase I/II studies. These compounds have generally been shown to have an acceptable toxicity profile and promising anti-tumor activity in heavily pretreated patients. The mechanisms of action of these compounds, as well as the potential therapeutic strategies to improve their efficacy are discussed in this review with particular regard to the combinations of anti-ErbB agents with cytotoxic drugs, or combinations of different ErbB-targeting agents.