Oncogenic growth factor receptors: implications for signal transduction therapy

Growth factors of the EGF family and their respective ErbB/HER receptor tyrosine kinases underlie many landmarks of tumor cells, including excessive growth, invasive behavior and attraction of blood vessels. Enhanced expression of ErbB proteins, existence of permanently active receptor mutants and occurrence of autocrine loops are frequently observed in human cancer, and in some cases they associate with poor disease outcome. The four ErbB proteins and their 11 ligands act within a layered signaling network coordinated by ErbB-2/HER2, the most oncogenic family member. Drugs that intercept signals emanating from ErbB-2 and ErbB-1 are already in routine clinical application. Here we review three major strategies to develop new ErbB-targeted therapies. These are monoclonal anti-receptor antibodies, specific tyrosine kinase inhibitors and antagonists of heat shock protein 90. The underlying mechanisms are critically examined, with an emphasis on potential drug combinations, which hold promise for enhanced clinical efficacy.