Gefitinib

Brand Name: Iressa

Gefitinib is used to treat non-small cell lung cancer.1

How Does Gefitinib Work?

Tyrosine kinase uses ATP to attach a phosphate tag on other proteins in a process called phosphorylation. This results in the transmission of growth signals.

Cellular growth signals are often transmitted through a process called phosphorylation, in which an enzyme called tyrosine kinase attaches a phosphate tag to another protein. This phosphate tag is derived from a molecule called ATP.2

EGFR protein on the surface of the cell.

EGFR is a protein in the receptor tyrosine kinase family. This protein consists of a receptor domain outside the cell connected to a tyrosine kinase domain inside the cell.3

Monomeric EGFR tyrosine kinase is inactive. Dimeric EGFR tyrosine kinase is active.

The kinase domain of EGFR is inactive by itself, but when two kinase domains come together to form a dimer, the kinase is activated. Active EGFR dimer then phosphorylates itself to transmit growth signals.4

Two EGFR proteins are separated on the surface of the cell.

In normal conditions, EGFR does not associate with each other and remains monomeric and inactive.4

Receptor binding to EGF results in EGFR dimerization.

On the other hand, in the presence of a growth factor called EGF3, the structure of the receptor domain of EGFR changes in a way that facilitates dimerization of EGFR.5,6

Active EGFR transmits growth signal through phosphorylation.

This brings two kinase domains of EGFR together and activates them to transmit growth signals through phosphorylation.4 Of note, because the dimerization of EGFR requires the binding of growth factors, growth signaling transmitted by EGFR is controllable; when cell growth is no longer necessary, growth factor production ceases, which returns EGFR to its inactive monomeric form.4

Dimerization-dependent and dimerization-independent EGFR mutants, which are both active in the absence of EGF.

In some types of cancer, a mutation in EGFR results in the activation of EGFR in the absence of growth factors. Some mutations cause EGFR to dimerize without growth factors, while other mutations cause the EGFR kinase to be active in its monomeric form.7 In either case, the kinases of EGFR are constitutively active.

Gefitinib blocks the ATP-binding site of EGFR and stops growth signal transmission.

Gefitinib is a type of drug called a kinase inhibitor. It blocks the kinase domain of EGFR from accessing the ATP required for phosphorylation.8 This turns off the growth signal, and as a result, cancer growth is halted.

References

1. IRESSA - Label. U.S. Food and Drug Administration (2021).

2. Hubbard, S. R. & Till, J. H. Protein Tyrosine Kinase Structure and Function. Annual Review of Biochemistry 69, 373-398 (2000).

3. Ullrich, A. et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309, 418-425 (1984).

4. Schlessinger, J. & Ullrich, A. Growth factor signaling by receptor tyrosine kinases. Neuron 9, 383-391 (1992).

5. Ogiso, H. et al. Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular Domains. Cell 110, 775-787 (2002).

6. Ferguson, K. M. et al. EGF Activates Its Receptor by Removing Interactions that Autoinhibit Ectodomain Dimerization. Molecular Cell 11, 507-517 (2003).

7. Cho, J. et al. Cetuximab Response of Lung Cancer-Derived EGF Receptor Mutants Is Associated with Asymmetric Dimerization. Cancer Research 73, 6770-6779 (2013).

8. Wakeling, A. E. et al. ZD1839 (Iressa): An Orally Active Inhibitor of Epidermal Growth Factor Signaling with Potential for Cancer Therapy. Cancer Research 62, 5749-5754 (2002).