One particular molecular target of high promise in oncology is the epidermal growth factor receptor (EGFR).

1. EpidermalGrowthFactor
Receptor(EGFR)Inhibitors
Bholakant Raut
Master in Pharmaceutical Engineering
China Pharmaceutical University

2. Introduction
• Molecular targeting strategies for cancer therapy are distinct from
conventional chemotherapy and radiotherapy in their potential to
provide increased tumor specificity.
• One particular molecular target of high promise in oncology is the
epidermal growth factor receptor (EGFR).

3. EGFR structure and function
• EGFRs are transmembrane receptors/proteins present on the cell membranes.
• The EGFR is a member of the ErbB family of receptors, a subfamily of four closely related
receptor tyrosine kinases: EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3) and
HER4 (erbB-4).
• They have an extracellular binding component/domain, a hydrophobic transmembrane
component/domain and an intracellular tyrosine kinase component/domain.
• EGFRs play an important role in controlling normal cell growth, apoptosis and
other cellular functions. Activation of the receptor is also important for the innate immune
response in human skin.

5. • EGFR is activated by binding of its specific ligands,
including EGF and TGF-α.Upon activation by its growth factor ligands,
EGFR undergoes a transition from an inactive monomeric form to an
active homodimers.
• EGFR may pair with another member of the ErbB receptor family,
such as HER2 (erbB-2/neu), to create an activated heterodimer.

6. • EGFR dimerization stimulates its intrinsic intracellular protein-
tyrosine kinase activity. As a result, autophosphorylation of
several tyrosine (Y) residues in the C-terminal domain (Y992, Y1045,
Y1068, Y1148 and Y1173) of EGFR occurs.
• This autophosphorylation elicits downstream activation and initiate
several signal transduction cascades leading to DNA synthesis,cell
proliferation, cell migration, adhesion, apoptosis, angiogenesis etc.

7. • Changes to the EGFRs gene (overexpressed, dysregulated or mutated),
however, can lead to continual or abnormal activation of the
receptors causing unregulated cell division, which can account
for some types of cancers.
• An EGFR inhibitor is a type of biological therapy that might stop
cancer cells from growing.

8. Two predominant classes of EGFR inhibitors have
been developed including:
• The most clinically advanced approach to EGFR inhibition includes
the use of monoclonal antibodies (mAbs) and the use of small
molecule tyrosine kinase inhibitors (TKIs).
• The mAbs is directed against the EGFR extracellular domain, whereas
the small molecule TKIs is directed against the tyrosine kinase
domain.

9. mAb EGFR inhibitors (Cetuximab)
• Some of the mAb inhibitors are cetuximab, ABX-EGF, EMD 72000, MDX-
447 etc.
• The most extensively studied of the anti-EGFR mAbs is cetuximab,
formerly known as IMC-225 or C225, a chimeric mAb designed to
specifically inhibit EGFR.
• Cetuximab has been recently approved (February 2004) by the US Food and
Drug Administration and the Swiss Medicines Control Agency for the
treatment of colorectal cancer.

10. • The Cetuximab was developed by combining the variable regions of
the precursor mouse antibody (mAb 225) with human
immunoglobulin G1 constant regions.
• This antibody is highly specific for EGFR, competing for natural
ligand-binding sites and causing receptor internalization and
downregulation. It inhibits the proliferation of a range of human tumor
cell.

11. Mechanisms of action of EGFR inhibitors
mAbs directed against EGFR have the following mechanisms of
action:
(i) extracellular binding;
(ii) internalization of receptor–antibody complexes;
(iii) inhibition of EGFR signaling pathways; and
(iv) potential stimulation of an immunological response.

12. • This inhibition of cell proliferation reflects cell-cycle arrest in the G1
phase and/or an increase in apoptosis.
• Cetuximab inhibits vascular endothelial growth factor (VEGF)
production in epidermoid carcinoma cells, resulting in a reduction in
the number of tumor blood vessels; downregulation of VEGF.

13. References:
• Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of Cancer: The Next
Generation. Cell, 144, 646-674.
• Hanahan, D., & Weinberg, R.A. (2000). The Hallmarks of Cancer. Cell, 100,
57-70
• https://www.drugs.com/drug-class/egfr-inhibitors.html
• https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor
• A review on Epidermal growth factor receptor inhibition strategies in oncology
by P M Harari.
• MEDICAL POLICY – 5.01.603;Epidermal Growth Factor Receptor (EGFR)
Inhibitors.
• Anticancer Drug Development Unique Aspects of Pharmaceutical
Development by Ajit S. Narang and Divyakant S. Desai.

14. Thank you….

15. TKIs
• The TKIs are synthetic, mainly quinazoline-derived, low
molecular weight molecules that interact with the intracellular
tyrosine kinase domain of several receptors, including EGFR,
and inhibit ligand-induced receptor phosphorylation by
competing for the intracellular Mg–ATP-binding site (Ciardiello
2000).
• TKIs in clinical trials Gefitinib, OSI-774(Erlotinib HC1/Tarceva), CI-
1033, EKB-569 etc.
• Gefitinib is an orally active, low molecular weight, synthetic
anilinoquinazoline that inhibits several receptor, tyrosine
kinases, particularly EGFR.

16. TKIsdirected against EGFR have the following mechanisms
of action:
(i) intracellular binding;
(ii) prevention of tyrosine kinase activation; and
(iii) inhibition of EGFR signaling pathways.