Molecular Genetics and Metabolism 88 (2006) 114–122 www.elsevier.com/locate/ymgme 1096-7192/$ - see front matter  2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2005.12.014 Minireview Targeting of EGFR tyrosine kinase by ZD1839 (“Iressa”) in androgen-responsive prostate cancer in vitro Ilaria Bellezza a , Sergio Bracarda b , Claudia Caserta b , Alba Minelli a,¤ a Dipartimento di Scienze Biochimiche e Biotecnologie Molecolari, Sezione di Biochimica Cellulare, Università di Perugia, via del Giochetto, 06123 Perugia, Italy b Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Sezione Farmacologia, Università di Perugia, via del Giochetto, 06123 Perugia, Italy Received 2 November 2005; received in revised form 14 December 2005; accepted 15 December 2005 Available online 17 February 2006 Abstract EGFR, highly expressed in a variety of human malignancies, is correlated with poor tumour diVerentiation, high tumour growth and metastatic rate. EGF and several other ligands, such as transforming growth factor-, amphiregulin, heparin-binding EGF, and betacell- ulin, activate Ras/Raf mitogen-activated protein kinases (MAPKs) and phosphatidyl inositol 3'-kinase (PI3K)/Akt signalling pathways. Therefore, EGFR can regulate multiple processes, i.e., gene expression, cellular proliferation, angiogenesis, and inhibition of apoptosis, which contribute to the development of malignancy. In this review, we discuss the inhibition of EGFR by the speciWc tyrosine kinase inhibitor Iressa (ZD1839) focusing on its eVects in prostate cancer.  2006 Elsevier Inc. All rights reserved. Keywords: EGFR; Prostate cancer; GeWtinib; Bicalutamide EGFR and signalling pathways The epidermal growth factor receptor (EGFR) belongs to the HER (erbB) family of four closely related membrane receptors: EGFR, also known as HER-1 or c-erbB-1 (the Wrst member of this group to be described), HER-2/neu (erbB-2), HER-3 (erbB-3), and HER-4 (erbB-4). These receptors are 170 kDa transmembrane glycoproteins char- acterized by an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain with tyrosine kinase activity for signal transduction. Although structurally similar, the members of the HER family diVer substantially in their function. HER2 is the preferred recep- tor in dimerisation between diVerent HER types (heterodi- merisation), though to date no natural ligand exclusively binding to HER2 is known. Various ligands can bind with diVerent speciWcity to HER1, 3 and 4. HER3 has little or no tyrosine kinase activity hence is unable to initiate signalling processes when present in homodimeric form [1]. In healthy tissues multiple ligands, such as epidermal growth factor (EGF), transforming growth factor- (TGF- ), amphiregulin, heparin-binding EGF, and betacellulin, bind to and activate EGFR although EGF and TGF- are the preferred ligands [2]. The ligand and the dimerisation partner are important in determining the signalling cascade and the activation of other receptors which, in turn, can cross-talk with other substances such as hormones, lym- phokines, and neurotransmitters to inXuence EGFR-medi- ated processes [1–5]. Intrinsic protein tyrosine kinase activation and tyrosine autophosphorylation occurring after ligand binding and EGFR dimerisation led to phos- phorylated tyrosine kinase residues that serve as binding sites for the recruitment and phosphorylation of several intracellular substrates. These activate the major signalling routes of the HER family, such as the Ras-Raf mitogen- activated protein kinase pathway, the phosphatidyl inositol 3'-kinase (PI3K)/Akt pathway or the STAT (signal trans- duction and activator of transcription) pathway [6]. These * Corresponding author. Fax: +39 075 585 7442. E-mail address: albaminelli@virgilio.it (A. Minelli).