Review Key cancer cell signal transduction pathways as therapeutic targets Roberto Bianco a , Davide Melisi a , Fortunato Ciardiello b , Giampaolo Tortora a, * a Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universita ` di Napoli Federico II, Via S. Pansini 5, 80131 Napoli, Italy b Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale, Seconda Universita ` di Napoli, Napoli 80131, Italy ARTICLE INFO Article history: Received 23 June 2005 Accepted 19 July 2005 Available online 11 January 2006 Keywords: Cancer therapy Angiogenesis EGFR Targeted agents ABSTRACT Growth factor signals are propagated from the cell surface, through the action of trans- membrane receptors, to intracellular effectors that control critical functions in human can- cer cells, such as differentiation, growth, angiogenesis, and inhibition of cell death and apoptosis. Several kinases are involved in transduction pathways via sequential signalling activation. These kinases include transmembrane receptor kinases (e.g., epidermal growth factor receptor EGFR); or cytoplasmic kinases (e.g., PI3 kinase). In cancer cells, these signal- ling pathways are often altered and results in a phenotype characterized by uncontrolled growth and increased capability to invade surrounding tissue. Therefore, these crucial transduction molecules represent attractive targets for cancer therapy. This review will summarize current knowledge of key signal transduction pathways, that are altered in can- cer cells, as therapeutic targets for novel selective inhibitors. The most advanced targeted agents currently under development interfere with function and expression of several sig- nalling molecules, including the EGFR family; the vascular endothelial growth factor and its receptors; and cytoplasmic kinases such as Ras, PI3K and mTOR. Ó 2005 Elsevier Ltd. All rights reserved. 1. Introduction The past decade has witnessed a major leap in the under- standing of the molecular mechanisms involved in tumour pathogenesis and progression. Several signalling molecules that play a critical role in these processes have been identified and are now recognized as potential therapeutic targets. In parallel, a wide array of new agents of different classes and with diverse mechanisms of action has been synthesized and is now under clinical evaluation. The following short re- view highlights the most prominent signalling targets in the context of current drug development. 2. Epidermal growth factor receptor (EGFR) and HER2/ErbB-2 Growth factor peptides and their receptors are often overex- pressed in human cancer cells and are involved in cell prolif- eration, differentiation and survival. One of the most studied growth factor receptor systems is the HER (also defined erbB) family. This family consists of four distinct, but structurally similar, transmembrane tyrosine kinase (TK) receptors, named HER1/erbB-1 (better known as endothelial growth fac- tor receptor [EGFR]), HER2/erbB-2, HER3/erbB-3 and HER4/ erbB-4) [1]. 0959-8049/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2005.07.034 * Corresponding author: Tel.: +39 081 7462061; fax: +39 081 2203147. E-mail address: gtortora@unina.it (G. Tortora). EUROPEAN JOURNAL OF CANCER 42 (2006) 290 – 294 available at www.sciencedirect.com journal homepage: www.ejconline.com