Epidermal Growth Factor Receptor: Difference between revisions

[[Epidermal Growth Factor Receptor]] (EGFR or '''ERBB1''') is found on the cell surface and associates to homodimers upon binding of its ligands such as the Epidermal Growth Factor (EGF) to its extracellular domain.  The dimerization stimulates autophosphorylation of several tyrosine residues in the intracellular kinase domain which signal downstream transduction cascades.  A human '''EGFR-2 (HER-2 or ERBB2)''' is involved in breast [[Cancer|cancer]] and is a major target for breast cancer [[Pharmaceutical Drugs|therapeutics]].  See more details in [[Herceptin - Mechanism of Action]].  '''ERBB3''' uses neuregulin as a ligand. '''ERBB4''' is a closely related [[Receptor tyrosine kinases|receptor tyrosine kinase]].  

==Relevance==

==EGFR and Lung Cancer==

The binding of epidermal growth factor (EGF) to epidermal growth factor receptor (EGFR) results in the activation of its protein tyrosine kinase activity due to an induced dimerization of the receptor <ref name='sherrill'>pmid    8639530</ref>.  This binding of EGF to the EGF receptor is an essential part of the signal transduction pathway that occurs in cells.  This binding results eventually in cell division.  Problems in this pathway can result in cancerous cells and tumors that eventually can lead to death.  Therefore, understanding all parts of signal transduction is essential for understanding the cause of cancer and possible treatments of it.  When EGF binds to EGFR, it results in an activation of the receptor which causes a chain of signaling events that leads to cell proliferation.  This occurs by transmission of the signal across the plasma membrane because EGFR is a plasma membrane protein and in this sense a transmembrane receptor <ref name='sherrill'/>.  Although it is present in normal cells, EGFR is overexpressed in many types of tumor cell lines, and its activation also plays an important role in resistance to chemotherapy and radiation treatment which makes treatment of cancer even more difficult <ref name='herbst'>pmid    15142631</ref>.  Since overexpression of EGFR is an attribute of some cancers, it is a plausible idea to find EGFR inhibitors to decrease the activity of EGFR and therefore inhibit cell proliferation and help control the growth of cancer and tumors.  EGFR inhibitors have been developed and seem to contribute at times to the regression of tumors <ref name='herbst'/>.  

Tyrosine kinases in general control critical cellular activities through regulation of signal pathways <ref name='pao'>pmid    15329413</ref>.  This regulation is essential for controlling the cell and making sure it acts normally and goes through the normal cell cycle. However, when these kinases are mutated, they can lead to cancer as a result <ref name='pao'/>.  Mutations in EGFR as a result can also lead to cancers, and this is why understanding how EGFR works is an essential aspect for the treatment of certain cancers.  In cancer, cells divide rapidly without control and an uncontrolled or unregulated EGF receptor will and can result in uncontrolled cell division.  Therefore, inhibition of EGFR can be an essential part of controlling cancers caused by mutations in EGFR.

The real question to answer was why is [[Gefitinib]] effective against some tumors and not against others.  Through studying ten patients who showed response to gefitinib, 70% had mutations in exons 18-24 of EGFR using mutational profiling of exons 18-24 <ref name='pao'/>.  Of these 7 patients, six showed the exact same mutation at the critical ATP binding site of K745 (<scene name='Yousuf_Bahrami_sandbox_1/K745/1'>See K745</scene>) while the other patient showed a L858R mutation (<scene name='Yousuf_Bahrami_sandbox_1/858/1'>See L858</scene>) <ref name='pao'/>.  These two mutations seem to be the two prevalent mutations seen in patients that have shown responses to [[Gefitinib]].  Through studying 8 refractory tumors not affected by [[Gefitinib]], none of the eight showed any mutations in exons 18-24 of EGFR <ref name='pao'/>.  This shows the connection between a mutation in EGFR and its ability to be treated by [[Gefitinib]] which binds to the critical ATP binding site.  Many of these mutations occurred at the same ATP binding site.  Another drug, [[Erlotinib]], showed almost exactly the same results as [[Gefitinib]] <ref name='pao'/>.

EGFR inhibitors used in breast cancer treatment<br />

EGFR inhibitors used in pancreatic and small cell lung cancer treatment<br />

EGFR inhibitors used in renal cell carcinoma and kidney cancer treatment<br />

EGFR inhibitors used in renal cell carcinoma and gastrointestinal cancer treatment<br />

* See also [[Journal:JBSD:35|A Possible Strategy against Head and Neck Cancer: ''In Silico''. Investigation of Three-in-One inhibitors]]

== 3D Structures of Epidermal Growth Factor Receptor ==