The hallmark of cancer cells is the autonomous and dysregulated proliferation. The proliferation is promoted by uncontrolled production of growth factors or through abnormal, enhanced expression of specific proteins which are located on the cell membranes. Growth factors are able to bind on this enhanced expressed cell membrane proteins. Intracellular signals resulted from the previously described processes lead to proliferation of cancer cells, angiogenesis and metastasis.
One group of this transmembrane growth factor receptors is the EGFR (Epidermal growth factor receptor) familiy which includes 4 related proteins and 10 different ligands. After a ligand binds to a single chain EGFR, the receptor forms a dimer after autophosphorylation of the single chain. That results in a intracellular signal cascade that may lead to proliferation of cancer cells.
There are two classes of EGFR antagonists in clinical use: anti-EGFR monoclonal antibodies and small molecule EGFR tyrosine kinase inhibitors. Anti-EGFR monoclonal antibodies bind to the extracelullar domain of EGFR, whereas small molecule EGFR inhibitors compete reversibly with ATP to bind the intracellular catalytic domain of EGFR tyrosine kinase and inhibits the signaling cascades emanates from EGFR.
The different small molecule EGFR inhibitors can block specifically different EGFR like different monoclonal antibodies. Treatment with this two princips have been approved for metastatic non-small-cell lung cancer, colorectal cancer, squamous-cell carcinoma of head and neck and pancreatic cancer.
In approximately 15 – 30% of patients with non-small-cell lung cancer and 40-45% of patients with colorectal cancer appears resistance to EGFR antagonists. Activating mutations in the K-RAS gene, which results in EGFR-dependent activation of the mitogen-activated protein kinase pathway are found in this patients. Other resitance appearence are observed.
Appropriate selection of patients is a major challenge for the treatment because responses against cancer are observed in just 10-20% of the patient. The problem may be the unspecific choice of patients for the treatment. Cancer cells must express functional EGFR on their surface. Another studies are needed to detect the the most effective sequences and combinations of EGFR inhibitors to use with chemotherapy and other parallel treatment also with a toxicity assessment.
[1] Ciardiello F. EGFR Antagonists in cancer treatment; Review. The New England Journal of Medicine. 1160-1175 (2008 )
