EGFR INHIBITORS IN CANCER THERAPY

by Selleckchem | Aug 17 2012

EGFR AND DEVELOPMENT OF CANCER:
Among a variety of signal transduction pathways vital for cell survival, growth, and proliferation etc. EGFR pathway is considered to be quite important. Its importance has been judged by analyzing the processes like tumor development and some other diseases occurring due to uncontrolled growth of cells. Mostly EGFR signaling pathway malfunctioning has been linked with the development of such types of diseases in the body for example; colon cancer, breast and lung cancer [1] and with anal cancer, multiform Glioblastoma and epithelial cancer. Therefore targeting EGFR for cancer therapy is a feasible approach. This EGFR inhibiting strategy magnifies the HER-1 inhibitor and its importance [2]. These inhibitors have a very significant role in the patients’ survival from the disease [3]. Different EGFR agonists and antagonists are used for the purpose of unveiling the role of this molecule in the cell as well as looking for a most efficient EGFR inhibitor [4]. These inhibitors are available at a very reasonable price and can be bought for any purpose.

MODE OF ACTION EGFR INHIBITORS:
Discovery of an effective and efficient EGFR inhibitor involves the use of construction of library and then high throughput screening for the most efficient inhibitor. The use and research about EGFR inhibitors got stimulated due to the detailed knowledge of crystal structure of the molecule and determination of its functions [5]. Different assays are there for the assessment of efficiency of different inhibitors for example; FISH i.e., fluorescent in situ hybridization [6], for quantification use of avidin biotin assay [7], qPCR i.e., Real time PCR [8], enzyme immunoassay [9] and dual immmunocytochemical assay [10]. These assays are performed usually before and after the application of inhibitor. Erlotinib is one of the most popular examples of EGFR inhibitors that contains in its structure 4-anilinoquinazoline having the potential specific for EGFR [5]. Gefitinib is another example of EGFR inhibitor that has been successful in its clinical trials [11]. Some other examples include CP-358774, BIBW2992, U0126 and ZD1839 etc.

CLINICAL EVALUATION OF EGFR INHIBITORS
Different types of EGFR inhibitors are there that have been brought into clinical trials and most of them have been successful in their clinical trials for the treating various cancers and tumors for example Erlotinib is in phase III of clinical trials for use against NSCLC i.e., non-small cell lung cancer and pancreatic cancer. Cetuximab is used in patients suffering from colorectal cancer while Gefitinib was used against NSCLC and lung cancer. Promising results with good symptomatic and radiographic response was seen in these patients [11]. Gefitinib is has been studied in vitro in the cell lines of adinocarcinoma [12]. In phase II clinical studies related to Erlotinib, Patients’ survival and symptoms of cancer were seen improved after the use of Erlotinib in case of NSCLC [13]. Along with single administration, Erlotinib has also been used in combination with Bevacizumab in patients of NSCLC that gave very promising results in clinical trials of phase I and II [14]. BIBW2992 is a very famous EGFR/HER2 inhibitor that is irreversible in its action, has been used in pre-clinical models of cancer and showed promising results [15].

REFERENCES:
1. Lo HW, e.a., EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Research and Treatment, 2006.
2. Johnston JB, e.a., Targeting the EGFR Pathway for Cancer Therapy. Current Medicinal Chemistry, 2006.
3. Lo HW, e.a., Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival. British Journal of Cancer, 2006.
4. Zelenaia O, e.a., Epidermal Growth Factor Receptor Agonists Increase Expression of Glutamate Transporter GLT-1 in Astrocytes through Pathways Dependent on Phosphatidylinositol 3-Kinase and Transcription Factor NF-κB Molecular Pharmacology, 2000.
5. Stamos J, e.a., Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem., 2002.
6. Cappuzzo F, e.a., EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol, 2008.
7. Kawamoto T, e.a., Quantitative Assay of Epidermal Growth Factor Receptor in Human Squamous Cell Carcinomas of the Oral Region by an Avidin-Biotin Method. Cancer Science, 1991.
8. Luca AD, e.a., Detection of Circulating Tumor Cells in Carcinoma Patients by a Novel Epidermal Growth Factor Receptor Reverse Transcription-PCR Assay. Clin Cancer Res, 2000.
9. Kumar RR, e.a., Enzyme immunoassay of human Epidermal Growth Factor Receptor (hEGFR). Human Antibodies, 2001.
10. Sharma AK, e.a., A dual immunocytochemical assay for oestrogen and epidermal growth factor receptors in tumour cell lines. The Histochemical Journal 1994.
11. Kris MG, e.a., Efficacy of Gefitinib, an Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Symptomatic Patients With Non-Small Cell Lung Cancer: A Randomized Trial. JAMA., 2003.
12. Paez JG, e.a., EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. Science, 2004.
13. Soler RP, e.a., Determinants of Tumor Response and Survival With Erlotinib in Patients With Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 2004.
14. Herbst RS, e.a., Phase I/II Trial Evaluating the Anti-Vascular Endothelial Growth Factor Monoclonal Antibody Bevacizumab in Combination With the HER-1/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib for Patients With Recurrent Non-Small-Cell Lung Cancer Journal of Clinical Oncology, 2005.
15. Li D, e.a., BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene, 2008.

Cat.No.	Product Name	Information
S1023	Erlotinib HCl	Erlotinib HCl is an EGFR inhibitor with IC50 of 2 nM in cell-free assays, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.
S1025	Gefitinib	Gefitinib is an EGFR inhibitor for Tyr1173, Tyr992, Tyr1173 and Tyr992 in the NR6wtEGFR and NR6W cells with IC50 of 37 nM, 37nM, 26 nM and 57 nM, respectively. Gefitinib promotes autophagy and apoptosis of lung cancer cells via blockade of the PI3K/AKT/mTOR pathway.
S1011	Afatinib	Afatinib inhibits EGFR/ErbB irreversibly in vitro with IC50 of 0.5, 0.4, 10, 14, 1 nM for EGFR^wt, EGFR^L858R, EGFR^L858R/T790M ErbB2 (HER2) and ErbB4 (HER4), respectively. Afatinib induces autophagy.
S1102	U0126-EtOH	U0126-EtOH is a highly selective inhibitor of MEK1/2 with IC50 of 0.07 μM/0.06 μM in cell-free assays, 100-fold higher affinity for ΔN3-S218E/S222D MEK than PD98059. U0126 inhibits autophagy and mitophagy with antiviral activity.