Novel anticancer targets: revisiting ERBB2 and discovering ERBB3

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Abstract
The Erbb family consists of four closely related type 1 transmembrane tyrosine kinase receptors: the epidermal growth factor receptor (EGFR; also known as ERBB1), ERBB2, ERBB3 and ERBB4. Signalling through the Erbb family underpins many of the cellular activities on which cell survival and function depend. EGFR, ERBB2 and ERBB3 are all implicated in the development and progression of cancer, and heterodimerization of the receptors plays a crucial part in their function. The role of ERBB4 in oncogenesis is less clear and this receptor might be involved in inhibition of cell growth rather than proliferation. Aberrant ERBB2 expression or function has been implicated in the evolution of both breast and gastric cancers and is evident in other cancer types, including ovarian and salivary gland tumours. This receptor has proved to be a potent target for anticancer therapies, including antibody-based therapies to prevent ligand binding, dimer formation or antibody-dependent cell-mediated cytotoxicity, and direct kinase inhibition to prevent molecular activation and recruitment of downstream signalling partners. New strategies against ERBB2 include Erbb tyrosine kinase inhibitors, heat shock protein 90 inhibitors, Erbb dimerization inhibitors and antibody–chemotherapy conjugates. All of these approaches have shown substantial clinical activity in patients who have progressed on trastuzumab, an anti-ERBB2 monoclonal antibody. The extent of the role of ERBB3 is now emerging and considerable research efforts are focused on developing new therapies that target ERBB3. ERBB3-specific monoclonal antibodies are now under evaluation, and data suggest that individual tyrosine kinase inhibitors might inhibit ERBB3 activation or its interaction with downstream signalling components. Preventing the dimerization of ERBB3 with its signalling partners, in particular ERBB2 with which it forms the most potent mitogenic signalling dimer, might offer an effective method of preventing oncogenic signalling across the Erbb network.