Target Analysis of Human EGFR

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein belonging to the erbB family of receptor tyrosine kinases. Binding of EGFR to its cognate ligands leads to autophosphorylation of the receptor tyrosine kinase and phosphorylation of numerous effector molecules subsequently resulting in signal transduction. EGFR signaling is very tightly regulated in normal cells. Aberrant activation of EGFR promotes processes responsible for tumor growth and progression, including proliferation, maturation, angiogenesis, invasion, metastases and inhibition of apoptosis. Overexpression of EGFR is observed in a variety of tumors and is associated with poor prognosis and decreased survival.

EGFR gene amplification, somatic mutations, overexpression or self production of ligands by the cell could result in cellular transformation by EGFR. A large number of somatic mutations and chromosomal aberrations have been reported in EGFR in several tumor types. These mutations result in constitutive activation of EGFR resulting in uncontrolled cell division - a predisposition for cancer. Some of the mutations are considered to be predictive markers for response to treatment with certain anti-EGFR inhibitors.

The central role of EGFR in cell proliferation, survival and metastasis coupled with its enhanced expression cancer, makes it an attractive molecular target for cancer therapy. Several approaches have been developed that target EGFR to interfere with EGFR-mediated cellular effects. The two most extensively studied approaches are the use of monoclonal antibodies directed against the extracellular receptor domain and small-molecule compounds that interfere with intracellular EGFR tyrosine kinase activity. Cetuximab and Panitumumab are among the FDA approved anti-EGFR monoclonal antibodies for colorectal cancer and squamous cell carcinoma of head and neck. In addition, several other anti-EGFR antibodies are undergoing various phases of clinical trials for different cancers. Small molecule tyrosine kinase inhibitors are another class of orally administered anti-EGFR agent. Erlotinb is an FDA approved inhibitor in treating non-small cell lung cancers and pancreatic cancers. Few other tyrosine kinase inhibitors, like Lapatinib, Canertinib, are in various phases of clinical trials. These drugs are effective as mono-therapy or in combination with chemotherapy or radiation therapy depending on the cancer type and treatment.

In this report, we analyze the EGFR gene with respect to its pharmacogenetic properties. The areas of focus include:

• Gene summary
• Orthologs and paralogs
• Alternate transcription
• Expression
• SNP analysis
• Other genetic alterations
• Promoter analysis
• Protein domains
• Disease

Table of Contents

1. Gene Summary - 4

2. Orthologs of EGFR - 5
 
3. Alternate transcription in EGFR - 10
  3A. Alternate transcription in humans - 10 
  3B. Alternate transcripts of EGFR in rodents - 23

EGFR expression in normal tissues - 23
  4A.Human EGFR expression - 23
  4B.Mouse EGFR expression - 32

5. SNPs in EGFR - 33
  5A. EGFR SNPs in humans - 33
  5B.Coding region SNPs- location and type - 35
  5C.Discussion of coding region SNPs - 36
  5D.EGFR SNPs in mouse - 39

6. Other genetic alterations of the EGFR gene - 40
  6A.Mutations - 42
    I. Mutations in tyrosine kinase domain - 43
    II. Mutations in the extracellular domain - 51
    III. Mutations in the C-terminal region - 55
    IV. Tandem duplications in EGFR - 56
    V. Germline mutations in EGFR - 57
Targeted mouse mutants of EGFR - 57
6B.Methylation and acetylation - 60
6C.Chromosomal aberrations - 62
   Genomic rearrangement - 62
   Copy number alterations - 65
   LOH - 67
6D.miRNA targets in the EGFR gene - 67

7. Promoter - 69

8.Paralogs - 74

Executive Summaries and Sample Pages |  Sample Appendix