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Medical Pharmacology Chapter 33-34: Anticancer Drugs
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Targeted Anticancer Drugs:
Growth Factors and Cancer Cell Receptors:
Epidermal Growth Factor Receptor (EGFR) Inhibitors1
EGFR (Epidermal Growth Factor Receptor) belongs to a transmembrane receptor protein kinase family, ERbB.
This family is also described as ErbB1 or HER1 (human EGFR1).1
Epidermal growth factor receptors are needed for both growth and epithelial cell differentiation.
Upon binding to a region of EGFR family proteins at the external region (domain) two receptors associate (dimerizes).
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Furthermore, this action increases intracellular tyrosine kinase activity (at the intracellular domain).
Auto-(self) phosphorylation of particular tyrosine residues associated with the C-terminal tale of the receptor monomers is initiated.
These particular phosphotyrosines interact with various "adapter" protein thus activating signaling pathways including
MAPK (Mitogen-Activated Protein Kinase: a specific serine/threonine protein kinase)
PI3K/Akt ( PI3K phosphorylates and activates AkT which initiates numerous downstream actions. PI3K: phosphotidylinositol-3-kinase, lipid kinase; Akt: also known as protein kinase B, PKB)
STAT (JAK-STAT signaling pathway. JAK: Janus kinases; STAT (Signal Transducer (and) Activator of Transcription Proteins)1
EGFR mutations that increase downstream signaling pathway activity confer a growth/survival benefit for cancer cells.1
Furthermore,
also conferred is the sensitivity to pharmacological intervention using
tyrosine kinase inhibitors (TKIs), such as:
Gefitinib (Iressa)
Activating EGFR mutations have been identified as frame deletions and a missense mutation.
Resistance to tyrosine kinase inhibitors may develop by acquisition of subsequent mutations, particularly by a mutation in the "gatekeeper" threonine790 residue (Thr790) i.e. T790M. 1,3
EGFR and HER2 are membrane-bound tyrosine kinases, closely related. EGFR expression in solid tumors (breast, lung, bladder, oral cavity, esophagus) is associated with reduction in life expectancy.
Nearly all epithelial-derived cancers exhibit EGFR expression.3
HER2 overexpression is a prominent characteristic of treatment-resistant breast, ovarian, gastric, and lung cancers.3
Drugs that target the EGFR pathway have been classified into two distinct classes:
Protein kinase inhibitors and
Inhibitors of extracellular ligand binding.
Those inhibitors that associate with the intracellular tyrosine kinase region, inhibiting the enzymatic activity of epidermal growth factor receptors include:
Gefitinib (Iressa)
Erlotinib (Tarceva)
Afatinib (Gilotrif).
Osimertinib (Tagrisso)
Other
inhibitors, monoclonal antibodies, bind to the extracellular region
of the EGFR thus diminishing ligand-induced activation. Examples
include:
Cetuximab (Erbitux)
Panitumumab (Vectibix)
Necitumumab (Portazza)
These agents promote an immune response.1
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