Epidermal Growth Factor Receptor: Difference between revisions
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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. | 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. | ||
[[Gefitinib]] is an inhibitor of EGFR, and it is used to treat some cancers especially non-small cell lung cancers (NSCLC) <ref name='pao'/>. If one is able to inhibit the ability of EGF to bind to its receptor, one can control the rate of cell division in tumor cells caused by mutations or problems in EGFR. | [[Gefitinib]] is an inhibitor of EGFR, and it is used to treat some cancers especially non-small cell lung cancers (NSCLC) <ref name='pao'/>. If one is able to inhibit the ability of EGF to bind to its receptor, one can control the rate of cell division in tumor cells caused by mutations or problems in EGFR. [[Gefitinib]] binds to EGFR at its highly important ATP binding activation site which is located at lysine 745 <ref name='pao'/>. When [[Gefitinib]] binds to this ATP binding site, it obviously does not allow for ATP to attach and phosphorylate in order to activate EGFR (<scene name='Yousuf_Bahrami_sandbox_1/Egfr_binded_to_gefitinib/1'>Gefitinib bound to EGFR</scene>). If ATP cannot bind, less EGF receptors will be activated and therefore this should help inhibit cell division in tumor cells and even cause regression. According to a study with two phase trials, regression of tumors were found in 28% of patients treated in Japan and 10% of those treated in Europe and U.S.A. <ref name='pao'/>. | ||
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'/>. | 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'/>. | ||