[Frontiers in Bioscience 17, 2698-2724, June 1, 2012] Expression pattern and targeting of HER family members and IGF-IR in pancreatic cancer Nikolaos Ioannou1, Alan M. Seddon1, Angus Dalgleish2, David Mackintosh1, Helmout Modjtahedi1 1School of Life Sciences, Kingston University London, Kingston, UK, 2Department of Cellular and Molecular Medicine, St George's University of London, London, UK TABLE OF CONTENTS 1. Abstract 2. Introduction 3. HER/ErbB family members and their ligands in pancreatic cancer 3.1. Structure and function of HER/ErbB family members and their ligands 3.2. Expression pattern and prognostic significance of EGFR (HER-1) and its ligands in pancreatic cancer 3.3. Expression pattern and prognostic significance of HER-2 in pancreatic cancer 3.4. Expression pattern and prognostic significance of HER-3 and HER-4 in pancreatic cancer 4. HER family of receptors as therapeutic targets in pancreatic cancer 4.1. EGFR targeting 4.1.1. Anti-EGFR mAbs 4.1.1.1. Cetuximab 4.1.1.2. Panitumumab 4.1.1.3. Matuzumab. 4.1.1.4. Nimotuzumab 4.1.2. EGFR Tyrosine kinase inhibitors 4.1.2.2. Erlotinib 4.1.2.3. Gefitinib 4.2. HER-2 targeting 4.3. HER-3 targeting 4.4. Dual and Pan-HER inhibitors 5. Predictive value of EGFR for response to EGFR inhibitors 6. Mechanisms of resistance to EGFR targeted therapy in pancreatic cancer 6. 1. The role of EGFR mutations in drug resistance. 6. 2. Activation of downstream pathways in an EGFR-independent manner 6. 3. Activation of alternative pathways 7. IGF-IR signalling system in pancreatic cancer 7.1. Expression and prognostic significance of IGF signalling system in pancreatic cancer 7.2. Targeting of IGF signalling system in pancreatic cancer 8. Perspective 9. Acknowledgments 10. References 1. ABSTRACT strategies. Such strategies could ultimately help to overcome the development of drug resistance and Pancreatic cancer is still one of the most improve the overall survival rates for patients with aggressive and fatal types of human cancer . Survival pancreatic cancer. rates for patients with pancreatic cancer are extremely poor and one major contributing factor is the lack of 2. INTRODUCTION specific marker(s) for the early detection of pancreatic cancer. Indeed, the great majority of pancreatic cancer Pancreatic cancer is one of the deadliest human cases are diagnosed at an advanced stage of the disease cancers and a major health problem worldwide. There were and these patients often have a poor response to an estimated 277.000 new cases of pancreatic cancer and treatment with conventional forms of therapy. In this 266.000 deaths from this cancer globally in 2008 (1). article, we conduct a comprehensive review of the Despite the introduction of new therapies in the last two literature on the expression pattern, prognostic decades, the collective median survival rate for patients significance and predictive value of EGFR family with pancreatic cancer remains poor and is less than 6 members, IGF-IR and their ligands in pancreatic cancer. months (2, 3). Several factors have been associated with an We also discuss recent advances in pancreatic cancer increased risk of developing pancreatic cancer including treatments and highlight the remaining challenges as age (above the age of 50), male sex, smoking, presence of well as future opportunities for more effective targeting medical conditions like diabetes and chronic pancreatitis, of such receptors using a combination of growth factor family history, occupational exposure to carcinogens, race receptor specific monoclonal antibodies, small molecule (higher incidence in black population) and high caloric tyrosine kinase inhibitors and other therapeutic consumption/obesity (4). 2698 HER family members and IGF-IR in pancreatic cancer There are numerous histological sub-types of survival, differentiation and apoptosis (16). In contrast to pancreatic cancer but the most common (90%) and hormones, growth factors are secreted by almost all tissues aggressive type is pancreatic ductal adenocarcinoma. The and mediate their effects by binding to their cell surface majority of pancreatic lesions (60-70%) arise in the head, receptors via paracrine, autocrine and/or juxtacrine neck or the uncinate process of the pancreas and the processes (17, 18). Activation of the cellular receptors by remaining 5-10% and 10-15% of all cases occur in the body their respective ligands results in the generation of signals and tail respectively (5). The high mortality rate that which are carried out by several intracellular signalling accompanies this type of cancer is mainly due to the proteins, ultimately leading to the different biological presence of metastases in the majority of patients at the responses by the activation and/or repression of specific time of diagnosis. Since symptoms of the disease don’t sets of genes (18). Since the early 1990s, aberrant usually arise until the cancer is at an advanced stage, most expression and activation of growth factor receptor of the cases (85-90%) are considered to be unresectable and signalling pathways has been reported in a wide range of therefore the only therapeutic option available is palliative human cancers and in some cases has also been associated treatment (3). Indeed, of all pancreatic cancer cases, only 7.5% with a poorer prognosis (17, 19). Such advances have of the cases are classified as localized lesions while 29.3% are resulted in the identification of novel therapeutic targets, locally advanced and 47.2% are metastatic. The 5-year shifting the interest of cancer researchers from traditional survival rate for patients with localized lesions is 15.2% while chemotherapy to targeted (14, 20). for locally advanced and metastatic disease is 6.3% and 1.6% respectively (6). In addition to palliative surgery, At present, there are 58 known human receptor chemotherapy is also used to alleviate symptoms and, in some tyrosine kinases (RTKs) which have been divided into 20 patients, it can also prolong survival (7). Until 1997, 5- subfamilies (18). One of the best characterised RTK Fluoracil (5-FU) had been the only drug with clinical benefit in subfamily is the ErbB family which consists of four pancreatic cancer. The introduction of gemcitabine prolonged members namely; EGFR (also known as ErbB1/HER-1), median survival by approximately one month (5.65 vs 4.41 ErbB2 (neu/HER-2), ErbB3 (HER-3) and ErbB4 (HER-4) months, P=0.0025) and improved disease symptoms with a (21-23). All family members share a similar structure clinical benefit response rate of 23.8% compared to 4.8% of 5- comprising of a ligand-binding extracellular domain, a FU (P=0.0022) (8). As a result, gemcitabine was approved by transmembrane domain and a large cytoplasmic region with the United States Food and Drug Administration (FDA) for the tyrosine kinase activity. Interestingly, there are no known treatment of pancreatic cancer in May 1996 and since then, ligands for HER-2, while HER-3 has been characterized as despite numerous combinations of gemcitabine with other a tyrosine kinase-inactive receptor (21, 22, 24). However, agents in clinical trials, only erlotinib has been added to the recent evidence suggests that HER-3 is actually able to weaponry against advanced pancreatic cancer (9, 10). Erlotinib catalyse phosphorylation but with a much weaker efficacy (Tarceva), an epidermal growth factor receptor (EGFR) compared to the other HER family members (25, 26). To tyrosine kinase inhibitor (TKI), was the only agent which led date, 11 different growth factors have been identified which to a modest, but statistically significant, improvement in have the ability to bind to the extracellular domain of the median survival when used in combination with gemcitabine ErbB family members. These growth factors are compared to gemcitabine monotherapy (10, 11). categorized into three different groups based on their receptor specificity. The first group of ligands which bind The inefficiency of cytotoxic agents in the only to EGFR, consists of epidermal growth factor (EGF), treatment of pancreatic cancer is primarily due to the transforming growth factor-α (TGF-α), amphiregulin (AR) intrinsic drug resistance that characterizes pancreatic cancer and epigen (EPG); the second group of ligands, which (12). The lethal nature of the disease, combined with the binds to both EGFR and ErbB-4, includes epiregulin minimal improvement in prognosis and treatment during (EPR), betacellulin (BTC) and heparin-binding EGF (HB- the last decades, dictates the importance of the EGF). Neuregulins (NRGs), the third group, is divided into development of new therapeutic agents, as well as the two sub-groups; NRG-1 and NRG-2 which bind to both identification of more reliable tumour biomarkers for the ErbB-3 and ErbB-4 while NRG-3 and NRG-4 bind only to early diagnosis of pancreatic cancer, the categorization of ErbB-4 (27-29). The binding of a ligand to its respective different prognostic groups and for predicting the response receptor leads to conformational changes of the to therapy (13-15). The aim of this article is to review the extracellular domain which allow the formation of homo- role of the type-I growth factor receptor (also called HER, and/or heterodimers (30). The formation of dimers leads to ErbB) family and insulin-like growth factor receptor I the activation of the cytoplasmic kinase domains which in (IGF-IR) in the progression of pancreatic cancer and their turn results in the auto- and transphosphorylation of importance as prognostic and predictive biomarkers as specific tyrosine residues found on the C-terminal region of well as therapeutic targets in pancreatic cancer. each receptor. These phosphorylation events allow the recruitment of several intracellular proteins which contain a 3. HER/ERBB FAMILY MEMBERS AND THEIR Src homology 2 (SH2) or phosphotyrosine binding (PTB) LIGANDS IN PANCREATIC CANCER. domains like adaptor proteins Shc and Grb2, kinases like Src and phosphatidylinositol 3 kinase protein (PI3K) and 3.1.