The interface between ErbB and non-ErbB receptors in tumor invasion: clinical implications and opportunities for target discovery

The molecular switches by which malignant cancer cells evolve from a confined to an invasive state are poorly understood, but seem to involve a progressive activation of a signaling network shared by several growth factor receptors and non-receptor molecules. Abnormal expression of ErbB tyrosine kinase receptors, commonly seen in cancer, is an early event in the invasive process, which makes these receptors exciting targets for drug discovery. The past few years have been full of promise for ErbB targeting in the context of receptor overexpression, but also fraught with disappointment as clinical efficacy has often been hampered by potential problems such as the heterogeneity of receptor expression within the same tumor, and the extensive cooperative signaling among ErbB and non-ErbB receptors. Cooperative signaling is a common characteristic of invasive cancer cells, and is believed to dictate the genetic program that controls invasion switches. Molecular studies on the combinatorial signaling involved in tumor invasion are becoming a fertile area for target discovery in cancer. This review discusses how cooperative signaling between ErbB and non-ErbB receptors regulates tumor invasion and hence provides multiple opportunities for drug discovery, and how current therapies and investigational drugs could pave the way to even more potent alternative combinatorial therapeutic approaches for invasive cancers. (C) 2003 Elsevier Science Ltd. All rights reserved.