Introduction: The HER (EGFR) pathway and Gefitinib

Protein kinases have been established in recent years as prime targets for selective inhibition in many disorders involving cell proliferation or cell migration. The extent of the protein kinase system is very large with hundreds of different proteins interacting together to send multitude of signals to nuclei determining growth, death, transcription or response to any form damage or stress. To enable understanding of the mechanism of action for all these proteins they have been classified under pathways which are directly related. One of these pathways that is significant in its effects is the HER pathway, originally known as the EGFR pathway in relation to the epithelial growth factor [1-4]. However, more proteins related to EGFR were recognized (ErRB 2-4) and the HER family was born. The location of this series of proteins is too span across the cell membrane from the extracellular region (head) into the cytosole (tail). Attachment of ligands to the extracellular sites cause structural changes to the protein which expose tyrosine kinase binding domains in the section of the protein located in the cytosole. [1;5;6]. Auto-phosphorylation occurs which initiates activity, protein are attracted to the binding domain where phosphorylation occurs transferring the conformational change to the next protein in the desired sequence. This cascade continues until the signal reaches the correct part of the nucleus whereby the program function occurs be it life or death. [7]. Of the many possible pathways that could be triggered the PI-3K, the RAS or the JAK pathway are the most significantly affected. Since these pathways are heavily involved in the regulation of the cell proliferation, migration or apoptotic events they are prime targets for an inhibitory intervention [4;8]. Gefitinib was designed specifically for this purposes based on the structure and Clinical experience of Imatinib [9;10].

Gefitinib: Properties and Availability

The Gefitinib EFGR inhibitor has been approved for use in NSCLC after failure of first line platinum treatment since 2003. It is manufactured and marketed by AstraZenica using the product name Iressa but it has been also researched under the code ZD1839. The Gefitinib structure consists of an anilinoquinazoline containing both a chloro and a fluoro substitution. Gefitinib is a specific inhibitor of EGFR with Gefitinib IC50 of approximately 0.4nM. Gefitinib had a much less potent activity against ErbB-2 (0.87 µM) and ErbB-4 (1.1 µM) [11], gefitinib has also demonstrated significant activity against EGFR mutations EGFRT1173 and EGFRT992 with IC50’s in the 40-50 nM range [12]. Gefitinib solubility in DMSo is fair up to a maximum of 100mg/ml but is considered poorly soluble in both water and ethanol. Gefitinib stability of the solid form -20oC is reported as being good, expiration of 2 years is recommended. Laboratories can buy Gefitinib from several reliable Gefitinib suppliers, however Gefitinib cost can be variable since Gefitinib prices can range from $89 up to $900.

Gefitinib: Preclinical investigations

Initial investigations with Gefitinib revealed reversible growth inhibition in a wide range of tumor cell lines and tumor xenografts [13]. Further research established Gefitinib as a potent chemotherapy agent in prostate [14;15], pancreatic [16], NSCLC [17;18] and breast cancer [19-22]. Cell type correlation demonstrated that HER2 over expressing cell lines were more sensitive to gefitinib treatment [23]. An investigation into 23 NSCLC cell lines demonstrated that gefitinib had significant anti-tumor activity in certain cell lines that correlated to EGFR copy number and EGFR gene mutations. With extensive research into the anti-tumor activities of gefitinib fast track approval was applied for and achieved in 2003 for NSCLC. However, in 2005 this approval was restricted to patients whom had already shown benefit for the treatment or already enrolled in a clinical trial. The reason for this restriction was due to two phase III trials cited prospectively in the original approval failed to meet their end points [24-26].

Gefitinib: Clinical status after NSCLC

There are multiple Gefitinib clinical trials in a variety of tumor types. Gefitinib is demonstrating clinical benefits in combinational therapy with previous chemotherapy drugs but as a single agent gefitinib consistently fails to meet target end points. The difference between in vitro and in vivo evidence is currently unexplained but several reports indicate that pharmacokinetic [27;28] / pharamcodynamic [27] / pharamcogenomic [29-31] issues may lie behind these problems.



    1.    Arteaga C. Targeting HER1/EGFR: a molecular approach to cancer therapy. Semin Oncol 2003; 30(3 Suppl 7):3-14.

    2.    Wells A. EGF receptor. Int J Biochem Cell Biol 1999; 31(6):637-643.

    3.    Maihle NJ, Baron AT et al. EGF/ErbB receptor family in ovarian cancer. Cancer Treat Res 2002; 107:247-258.

    4.    Brandt B, Meyer-Staeckling S et al. Mechanisms of egfr gene transcription modulation: relationship to cancer risk and therapy response. Clin Cancer Res 2006; 12(24):7252-7260.

    5.    Adamson ED, Wiley LM. The EGFR gene family in embryonic cell activities. Curr Top Dev Biol 1997; 35:71-120.

    6.    Baselga J. A review of EGFR targeted therapy. Clin Adv Hematol Oncol 2003; 1(4):218-219.

    7.    Bishayee S. Role of conformational alteration in the epidermal growth factor receptor (EGFR) function. Biochem Pharmacol 2000; 60(8):1217-1223.

    8.    Ferrer-Soler L, Vazquez-Martin A et al. An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: Gefitinib (Iressa) -induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review). Int J Mol Med 2007; 20(1):3-10.

    9.    Agelaki S, Georgoulias V. Epidermal growth factor receptor inhibitors in the treatment of non-small cell lung cancer. Expert Opin Emerg Drugs 2005; 10(4):855-874.

  10.    Blackledge G, Averbuch S. Gefitinib ('Iressa', ZD1839) and new epidermal growth factor receptor inhibitors. Br J Cancer 2004; 90(3):566-572.

  11.    Wood ER, Truesdale AT et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 2004; 64(18):6652-6659.

  12.    Pander J, Gelderblom H et al. Pharmacogenetics of EGFR and VEGF inhibition. Drug Discov Today 2007; 12(23-24):1054-1060.

  13.    Baselga J, Averbuch SD. ZD1839 ('Iressa') as an anticancer agent. Drugs 2000; 60 Suppl 1:33-40.

  14.    Peraldo-Neia C, Migliardi G et al. Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer. BMC Cancer 2011; 11:31.

  15.    Jain A, Penuel E et al. HER kinase axis receptor dimer partner switching occurs in response to EGFR tyrosine kinase inhibition despite failure to block cellular proliferation. Cancer Res 2010; 70(5):1989-1999.

  16.    Azzariti A, Porcelli L et al. Synergic antiproliferative and antiangiogenic effects of EGFR and mTor inhibitors on pancreatic cancer cells. Biochem Pharmacol 2008; 75(5):1035-1044.

  17.    Iressa : first angiogenesis inhibitor approved for the treatment of advanced NSCLC. Expert Rev Anticancer Ther 2003; 3(3):257.

  18.    Adamo V, Franchina T et al. Gefitinib in lung cancer therapy: clinical results, predictive markers of response and future perspectives. Cancer Biol Ther 2009; 8(3):206-212.

  19.    Agrawal A, Gutteridge E et al. Overview of tyrosine kinase inhibitors in clinical breast cancer. Endocr Relat Cancer 2005; 12 Suppl 1:S135-S144.

  20.    Ait-Tihyaty M, Rachid Z et al. Inhibition of EGFR phosphorylation in a panel of human breast cancer cells correlates with synergistic interactions between gefitinib and 5'-DFUR, the bioactive metabolite of Xeloda((R)). Breast Cancer Res Treat 2011.

  21.    Anido J, Matar P et al. ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. Clin Cancer Res 2003; 9(4):1274-1283.

  22.    Moulder SL, Yakes FM et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 2001; 61(24):8887-8895.

  23.    Moasser MM, Basso A et al. The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 2001; 61(19):7184-7188.

  24.    Vokes EE, Chu E. Anti-EGFR therapies: clinical experience in colorectal, lung, and head and neck cancers. Oncology (Williston Park) 2006; 20(5 Suppl 2):15-25.

  25.    Rigas JR, Lara PN, Jr. Current perspectives on treatment strategies for locally advanced, unresectable stage III non-small cell lung cancer. Lung Cancer 2005; 50 Suppl 2:S17-S24.

  26.    Ibrahim EM. Frontline gefitinib in advanced non-small cell lung cancer: Meta-analysis of published randomized trials. Ann Thorac Med 2010; 5(3):153-160.

  27.    Hoshino-Yoshino A, Kato M et al. Bridging from preclinical to clinical studies for tyrosine kinase inhibitors based on pharmacokinetics/pharmacodynamics and toxicokinetics/toxicodynamics. Drug Metab Pharmacokinet 2011; 26(6):612-620.

  28.    Leveque D. Pharmacokinetics of gefitinib and erlotinib. Lancet Oncol 2011; 12(12):1093.

  29.    Becquemont L, Alfirevic A et al. Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics. Pharmacogenomics 2011; 12(1):113-124.

  30.    de Mello RA, Marques DS et al. Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies. World J Clin Oncol 2011; 2(11):367-376.

  31.    Hansen NT, Brunak S et al. Generating genome-scale candidate gene lists for pharmacogenomics. Clin Pharmacol Ther 2009; 86(2):183-189.