Pres spring2009 john_leonard

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Pres spring2009 john_leonard

  1. 1. EGFR, A Mutation & Gefitinib By: John Leonard RBIF 102 Genomics and Genetics
  2. 2. Introduction The topic of this presentation is the EGFR gene and how a mutation can help identify a palliative treatment:  Epidermal Growth Factor Receptor  Signaling Pathway  The Gene EGFR  Hallmarks of Cancer  The L858R Mutation  Gefitinib  The Gefitinib Test RasTop rendering of 1M17.pdb
  3. 3. Epidermal Growth Factor Receptor The Epidermal Growth Factor Receptor; EGFR, ErbB-1, HER1 depending on the literature:  Member of the ErbB family of receptors, a subfamily of the epidermal growth factor family (EGF-family) of extracellular protein ligands.  First cell surface signaling protein to be characterized by molecular genetic methods.  Is a Tyrosine Kinases (TK) protein and as such regulate signaling pathways that control critical cellular activities.  Plays an important role in carcinogenesis and is therefore a target for cancer therapy.
  4. 4. EGFR Signaling Pathway Upon activation, EGFR undergoes transformation and forms an active homo- or heterodimer, which will initiate a distinct signaling pathway resulting in autophosphorylation, which in turn initiates a downstream cascade of events culminating in cellular responses; such as cell proliferation or apoptosis. http://www.biooncology.com/
  5. 5. The Gene EGFR EGFR/1956 found on chromosome 7 (7p12), all EGFR family members are characterized by a modular structure, with a highly conserved Tyrosine Kinase (TK) domain. The TK domain contains an Adenosine Triphosphate (ATP) binding region; ATP is referred to as the "molecular currency“.
  6. 6. The Gene EGFR Distribution of protein TK genes in the human genome (G-banded chromosome ideograms) The protein tyrosine kinase family of the human genome, Oncogene, 2000
  7. 7. The Hallmarks of Cancer From a paper entitled The Hallmarks of Cancer:  Cancer cells have defects in regulatory circuits that govern normal cell proliferation.  Cancer cells manifest six alterations in cell physiology, acting to breach the cell’s anticancer defense mechanism.  The evidence is mounting that resistance toward apoptosis is a hallmark of most, if not all types of cancer. The Hallmarks of Cancer. Douglas Hanahan & Robert A. Weinberg
  8. 8. The Hallmarks of Cancer Elevated expression and/or amplification of EGFR have been found in a variety of human cancers. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification, Endocrine-Related Cancer (2001)
  9. 9. The L858R Mutation The L858R substitution/point mutation:  A SNP, T>G which resulted in a modification of an amino acid from Leucine (hydrophobic/small) to Arginine (hydrophilic/large).  It is the most common point mutation within EGFR.  Non-Small Cell Lung Cancer (NSCLC) patients with the L858R mutation have been found to be responsive to treatment by selective inhibits, such as Gefitinib. Lung cancer accounts for 1 in every 3 cancer deaths and an average of 439 people every day from lung cancer.
  10. 10. The L858R Mutation L858R located in a mutation “hotspot” adjacent to a highly conserved region around the ATP binding cleft; T790M.
  11. 11. The L858R Mutation A study published in the Journal of the National Cancer Institute, analyzed 134 mutations detected in the TK domain of EGFR, identified 28 distinct mutations of three different types, all centered around the ATP binding cleft. Clinical and Biological Features Associated with Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers, Journal of the National Cancer Institute, March 2, 2005
  12. 12. The L858R Mutation Mutations around the ATP-binding site leading to a structural change in the protein structure, that in turn affect functions. “Mutation increases the sensitivity of the tumor to inhibitors of EGFR, most likely by repositioning critical residues surrounding the ATP-binding cleft of the tyrosine kinase domain of the receptor, thereby stabilizing their interactions with both ATP and its competitive inhibitors.” EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib, The New England Journal of Medicine, February 14, 2005
  13. 13. Gefitinib Gefitinib (originally coded ZD1839) is marketed by AstraZeneca and Teva under the trade name Iressa:  Gefitinib is a TK/ATP-competitive inhibitor, which binds to the ATP-binding site and inhibits kinase activity.  From Endocrine-Related Cancer, 2001 - “Another promising EGFR inhibitor, ZD-1839, which shows an antiproliferative effect in ovarian, breast and colon cancer cells is under clinical development”  Another ATP-competitive inhibitor marketed by Genentech and OSI Pharmaceuticals is Erlotinib.
  14. 14. Gefitinib To-date no crystal structure of the Gefitinib complex has been published, a model of this complex suggested that it has a conformation similar to Erlotinib. ErlotinibGefitinib http://www.rcsb.org/
  15. 15. The Gefitinib Test Gefitinib has had an interesting journey:  In 2004 AstraZeneca advised the Food and Drug Administration (FDA) that large scale studied of Gefitinib failed to demonstrate any survival advantages in treatment of NSCLC tumors.  In December 2006, Genzyme Corporation announced that it would make available a laboratory test to identify patients that would respond to treatment by Gefitinib and Erlotinib.  The hope is that this test will help Gefitinib and Erlotinib win regulatory approval as an initial therapy. Currently Gefitinib and Erlotinib is only used for patients that have failed one or more chemotherapy regimens. Is this a step towards personalized medicine?
  16. 16. References  http://www.biooncology.com/  http://www.ebi.ac.uk/  http://www.medicalnewstoday.com/  http://www.lungcanceralliance.org/  http://www.rcsb.org/pdb/  The Hallmarks of Cancer, Douglas Hanahan & Robert A. Weinberg, Cell, January 7, 2000  EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib, Susumu Kobayashi, M.D., Ph.D., Titus J. Boggon, Ph.D., Tajhal Dayaram, B.A., Pasi A. Jänne, M.D., Ph.D., Olivier Kocher, M.D., Ph.D., Matthew Meyerson, M.D., Ph.D., Bruce E. Johnson, M.D., Michael J. Eck, M.D., Ph.D., Daniel G. Tenen, M.D., and Balázs Halmos, M.D., The New England Journal of Medicine, February 14, 2005  EGF receptor gene mutations are common in lung cancers from ‘‘never smokers’’ and are associated with sensitivity of tumors to gefitinib and erlotinib, William Pao, Vincent Miller, Maureen Zakowski, Jennifer Doherty, Katerina Politi, Inderpal Sarkaria, Bhuvanesh Singh, Robert Heelan, Valerie Rusch, Lucinda Fulton, Elaine Mardis, Doris Kupfer, Richard Wilson, Mark Kris & Harold Varmus, PNAS, September 7, 2004  The protein tyrosine kinase family of the human genome, Dan R Robinson, Yi-Mi Wu & Su-Fang Lin, Oncogene, 2000  The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification, N Prenzel, O M Fischer, S Streit, S Hart & A Ullrich, Endocrine-Related Cancer (2001)  Clinical and Biological Features Associated with Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers, Hisayuki Shigematsu, Li Lin, Takao Takahashi, Masaharu Nomura, Makoto Suzuki, Ignacio I. Wistuba, Kwun M. Fong, Huei Lee, Shinichi Toyooka, Nobuyoshi Shimizu, Takehiko Fujisawa, Ziding Feng, Jack A. Roth, Joachim Herz, John D. Minna & Adi F. Gazdar, Journal of the National Cancer Institute, March 2, 2005
  17. 17. Thank You and Questions Please join my LinkedIn network at http://www.linkedin.com/in/johnmleonard.

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