egfr related to cancer

EPIDERMAL GROWTH FACTOR RECEPTOR: 

EPIDERMAL GROWTH FACTOR RECEPTOR SUBMITTED BY SHARATHBABU.THOTA 10T36S0114 UNDER THE GUIDANCE OF Mrs.HELEN SHEEBA D.A ,M.PHARMA. ASSIT.PROFESSOR DEPARTMENT OF PHARMACOLOGY MALLA REDDY INSTITUTE OF PHARMACEUTICAL SCIENCES

EGFR RECEPTOR’S: 

EGFR RECEPTOR’S CONTENTS INTRODUCTION TYPES OF EGFR EGFR-LIGANDS EGFR-SIGNALING PATHWAYS DISEASE RELATED TO EGFR TREATMENT REVIEW ARTICALES CONCULSION REFERENCES

INTRODUCTION: 

INTRODUCTION The epidermal growth factor receptor (EGFR) . The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands 1 Epidermal growth factor receptor (EGFR) , the founding member of family of four ErbB receptor tyrosine kinases, has been a focus of intense research since initial purification in 1982.

INTRODUCTION: 

INTRODUCTION EGF (Epidermal Growth Factor) is a small 53 amino acid residue protein that is involved in normal cell growth, oncogenesis, and wound healing. EGFR is a member of the ErbB (Erythroblastic Leukemia Viral Oncogene Homolog) family receptors, a subfamily of four closely related receptor tyrosine kinases:

EGFR STRUCTURE: 

EGFR STRUCTURE

TYPES OF EGFR : 

TYPES OF EGFR The EGFR family of receptor tyrosine kinases comprises the EGFR (ErbB1), ErbB2/HER2/ neu , ErbB3/HER3 and ErbB4/HER4 Binding of EGF to the extracellular domain of EGFR leads to receptor dimerization, activation of the intrinsic PTK (Protein Tyrosine Kinase) activity, tyrosine autophosphorylation, and recruitment of various signaling proteins to these autophosphorylation sites located primarily in the C-terminal tail of the receptor. Tyrosine phosphorylation of the EGFR leads to the recruitment of diverse signaling protein

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Ligands :for the ErbB family include EGF amphiregulin (AR) TGF-a  betacellulin (BTC), heparin-binding EGF (HB–EGF) epiregulin. Neuregulins 1 (NGR1)

EGFR PATHWAY: 

EGFR PATHWAY

THE RAS/ERK PATHWAY: 

THE RAS/ERK PATHWAY EGF activates the ERK pathway .Binding of Grb2 to phosphorylated ErbB receptors, which in turn results in the recruitment of the son of sevenless (SOS) to the activated receptor dimer. SOS then activates RAS leading to the activation of RAF-1. RAF-1 subsequently phosphorylates MEK1 and MEK2 which activate respectively ERK1 and ERK2. This pathway results in cell proliferation and in the increased transcription of Bcl-2 family members and inhibitor of apoptosis proteins (IAPs) , thereby promoting cell survival

RAS ISO FORMS : 

RAS ISO FORMS RAS ISO FORMS Ras proteins are Small GTPases 3 isoforms N- ras , H- ras , and K- ras (2 splice varients , K-ras4B here) Generate distinct signaling output. But interact with the same activators and downstream signaling points Differences are due to the c terminal 25 aa in the Hypervariable domain.

PI3 KINASE/AKT PATHWAY: 

PI3 KINASE/AKT PATHWAY EGF also promotes cell survival through the activation of PI3 kinase/AKT signaling . EGF triggers the recruitment of PI3 kinase to activated ErbB receptors, which is mediated by the binding of SH2 domains in PI3 kinase to phosphorylated tyrosine residues. The catalytic subunit of PI 3-kinase in turn phosphorylates phosphatidylinositol 4,5 bisphosphate leading to the formation of PtdInsP 3 . PI 3-kinase can also activate RAS

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Akt- Family members In humans, there are three genes "Akt family": Akt1, Akt2, and Akt3. These genes code for enzymes that are members of the non-specific serine/ threonine -protein kinase family Akt1 is involved in cellular survival pathways, by inhibiting apoptotic processes. Akt1 is also able to induce protein synthesis pathways, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the oncogene in the transforming retrovirus,

JAK/STAT PATHWAY: 

JAK/STAT PATHWAY

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Another signaling cascade initiated by EGF is the JAK/STAT pathway, which is also implicated in cell survival responses. JAK phosphorylates STAT proteins localized at the plasma membrane. This leads to the translocation of STAT proteins to the nucleus where they activate the transcription of genes associated with cell survival

ROLE OF EGFR: 

ROLE OF EGFR The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor. Binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. Mutations in this gene are associated with lung cancer

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The epidermal growth factor receptor The HER signaling pathway plays a role in the normal regulation of cell growth, proliferation, migration, and mediating processes, such as wound healing, tissue repair, and maintenance of the skin. In addition to its role in controlling the growth of normal cells, the HER signaling pathway has been shown to have a significant impact on the growth, proliferation, migration, and survival of cancer cells.

EGFR HYPERACTIVATION: 

EGFR HYPERACTIVATION

DISEASE RELATED TO EGFR : 

DISEASE RELATED TO EGFR EGFR SIGNALING PATHWAY IN BREAST CANCERS EGFR is considered as a major oncogenic factor and an attractive therapeutic target. The well-established traditional function of EGFR is known to transmit extra-cellular mitogenic signals, such as EGF and transforming growth factor-alpha (TGF-alpha), through activating a number of downstream signaling cascades. These include signaling modules that involve phospholipase C-gamma , Ras , and phosphatidylinositol-3 kinase (PI-3K). In cancer cells, the common outcomes following the activation of the EGFR-mediated downstream pathways are altered gene activities, leading to un-controlled tumor proliferation and apoptosis. breast cancer patients. While several anti-EGFR agents are being tested in breast cancer

BLADDER CANCER: 

BLADDER CANCER The expression of epidermal growth factor receptor (EGFR) was studied of. The expressions of p53 and EGFR were interrelated, while expression of c-erbB-2 was independent of EGFR expression. The results show that overexpression of EGFR is related to several malignant features and prognosis in superficial bladder cancer.

HEAD AND NECK CANCER: 

HEAD AND NECK CANCER EGF or transforming growth factor-alpha (TGF-α) results in activation of intracellular tyrosine kinase, therefore, cell cycle progression. High levels of EGFR expression are correlated with poor prognosis and resistance to radiation therapy in a variety of cancers. mostly in squamous -cell carcinoma of the head and neck (SCCHN). Blocking the EGFR by a monoclonal antibody results in inhibition of the stimulation of the receptor, therefore, in inhibition of cell proliferation, enhanced apoptosis, antisense therapies.

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RENAL CANCER- NF- κB - AKT pathway- (bortezomib) GLIOMA OVARIAN CANCER (tyrosine kinase inhibitor, gefitinib, cetuximab) PANCREATIC CANCER (Gemcitabine, 5-fluorouracil (5-FU) Erlotinib) COLON CANCER (Cetuximab,bevacizumab. Panitumumab)

EGFR MUTATIONS IN LUNG CANCER : 

EGFR MUTATIONS IN LUNG CANCER SMALL CELL LUNG CANCER NON SMALL CELL LUNG CANCER 1.Squamous cell carcinoma 2.Adenocarcinoma 3.Large cell carcinoma SQUAMOUS CELL CANCER Squamous cell cancer is the most common type of lung cancer. It develops from the cells that line the airways and it is often found near the centre of the lung in one of the main airways (the left or right bronchus).

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squamous cell lung cancer mainly caused by Smoking ADENOCARCINOMA Adenocarcinoma also develops from the cells that line the airways. But it develops from a particular type of cell that produces mucus (phlegm) LARGE CELL CARCINOMA Large cell lung cancer is called this because the cells look large and rounded under a microscope. This type of lung cancer tends to grow quite quickly.

IDENTIFICATION GENETIC MUTATION ANALYTICAL METHODOLOGIES: 

IDENTIFICATION GENETIC MUTATION ANALYTICAL METHODOLOGIES

  TREATMENT : 

TREATMENT

Gefitinib-AstraZeneca- Teva: 

Gefitinib- AstraZeneca- Teva

Mechanism of action: 

Mechanism of action Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the anti-apoptotic Ras signal transduction cascade is inhibited, and malignant cells are inhibited Clinical uses-NSCLC

Lapatinib-Tykerb/Tyverb- GSK: 

Lapatinib-Tykerb / Tyverb - GSK Clinical application Breast cancer Adverse effects diarrhea, fatigue, nausea and rashes. In ongoing studies the drug have shown to provoke toxic hepatitis, the toxicity.

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Panitumumab Panitumumab (INN), , is a fully human monoclonal antibody specific to the epidermal growth factor receptor Cetuximab Cetuximab (IMC-C225—marketed under the name Erbitux ) colorectal cancer and head and neck cancer Cetuximab is indicated for the treatment of patients with EGFR expressing. KRAS wild-type metastatic colorectal cancer in combination with chemotherapy

REVIEW ARTICAL : 

REVIEW ARTICAL 1. Vincet A.Miller et.al (2011) investigated that New Strategies in Overcoming Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Cancer .The data clearlyindicated that the most common being the development of an EGFR T790M gatekeeper mutation in more than 50% of cases. In this review, we discuss recent advances in the understanding of acquired TKI resistance in EGFR -mutant lung cancer and review therapeutic progress with second generation TKIs and combinations of targeted therapie s .

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2. Andrew B. Lassman , et. al;(2011) Pulsatile ” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer.The data indicated We previously reported that intermittent “ pulsatile ” administration of high-dose (1500 mg) erlotinib once weekly was tolerable and achieved concentrations in cerebrospinal fluid exceeding the half maximal inhibitory concentration for EGFR mutant lung Ref . British Journal of Cancer (2011) 99 , 911–922. doi:10.1038/sj.bjc.6604559 Published online 26 August 2011

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3. Prashasnika gehlot et.al., (2010) “ Pulsatile ” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer cancer cells in a patient with leptomeningeal metastases; we now expand this paradigm to a series of 9 patient We retrospectively identified patients with EGFR mutant lung cancer treated with pulsatile erlotinib for CNS metastases Ref. Clinical Cancer Researchclincancerres.aacrjournals.org

CONCLUSION: 

CONCLUSION EGFR one of most important growth factor binds to EGFR receptors epithelial cells which control the development and differentiation. The mutation in EGFR gene lead to abnormal formation of transcription product receptor protein deviating the normal pathway of activation of receptors which lead to development of cancer. After being identification of role of EGFR in development of different types cancer, development of therapy had initiated which mostly include monoclonal antibodies like transtuzumab etc. Another approach include EGFR receptor antagonists like gefitinib, Lapatinib erlotinib , which bind to receptors internal domain of EGFR preventing the binding of ATP which in turn leads to termination of signal transduction by agonist .

REFERENCE : 

REFERENCE 1 .Herbst Rs.”Review of epidermal growth factor receptor biology” on the .c2004. http://www.rerf.jp/general/whatis_e/index.html 2. Ullrich a, cosssens “c dna sequences and aberrant expression of the amplified gene in A 431 epidermal carcinoma cell nature “ .1984:418-425. 3 . Zhang H, Berezov A, wang Q, “ ErbB receptors:from ancogenes to targeted cancer therapies “.c( Augest 2007). 4.”Review of epidermal growth factor receptor biology “.c2004. Int.J.Radiant.oncol.Biol.phys.59 5.Herbst Rs .”Review of epidermal growth factor receptor biology” [home page on the internet].c2004. http://www.rerf.jp/general/whatis_e/index.html 6 . Oda K, Matsuoka Y, Funahashi A, Kitano H. " A comprehensive ligand pathway map of epidermal growth factor receptor signaling ". C(2005). mol.syst.Biol . 7.Walker RI, Cerveny RJ,eds .. RAS/extracellular signal regulated kinase [ Erk ] falls church,VA : office of the surgeon General; 1990. Available from;(http://www Affri.usuhs.mil.)

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8.Morgan Kj , Gilliand DG. A role for JAK2 mutations in myeloproliferative disease . Annu Rev Med.c2008. 9.Hunter T.”Protein kinase classification”.meth . Enzymol.c2000. 10.About Apoptosis” Apoptosis inter group, preferred pronunciation of National institute of Health Available from: (‘’http://www.nih. gov /sigs/ aig /Aboutapo.html) 11.Mc Cubrey JA, Steelman LS.”Roles of the Raf /MEK/ERK pathway in cell growth, malignant transformation and drug resistances’’ .c2008.Available form ;(http//www.gene.com/prodct/information.) 12. The role of N-region in the evalutitonaryof RAF kinase function in vertebrates.j Biol chem282, 26575-26590.available from: (http://www.sfb487.uniwuerzbug.de) 13.Liang K,Ang KK, Milas l,et al: The epidermal growth factor receptor mediates radioresistances . Int J Oncol Biol phys 57:246-254.c2003.Available from ;(http://www.gene.com/egfr_factsheet.html) 14.(http://www.licor.com/bio/products/reagents_egf.jsp

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