EGFR protein, a 170 kDa plasma membrane glycoprotein, is composed of an extracellular domain, a single hydrophobic transmembrane region, an intracellular portion that contains the C-terminal tail, and a TK domain that is important for signal transduction
EGFR protein, a 170 kDa plasma membrane glycoprotein, is composed of an extracellular domain, a single hydrophobic transmembrane region, an intracellular portion that contains the C-terminal tail, and a TK domain that is important for signal transduction.17 Upon ligand binding, a receptor TK undergoes a series of changes, the earliest one becoming the conversion of the monomeric form of the receptor to the dimeric form. intracellular portion that contains the C-terminal PKA inhibitor fragment (6-22) amide tail, and a TK website that is important for transmission transduction.17 Upon ligand binding, a receptor TK undergoes a series of changes, the earliest one becoming the conversion of the monomeric form of the receptor to the dimeric form. This prospects to activation of the kinase, resulting in phosphorylation of its own tyrosine residues, a trend known as autophosphorylation. The phosphotyrosine residues of the triggered receptor then act as docking sites for target molecules, such as signal transducers. This association causes off signaling cascades through pathways such as PI3-kinase-AKT, RAS/RAF, and PI3K-Akt and modulates cell proliferation, survival, adhesion, migration, and differentiation.18 EGFR tyrosine kinase inhibitor At present, EGFR-targeted drugs contain a monoclonal antibody, such as cetuximab, that targets the extracellular website of EGFR and the small-molecule EGFR TK selective inhibitor that targets the TK website in the intracellular portion and therefore blocks the signal transduction pathways implicated in PKA inhibitor fragment (6-22) amide the proliferation and survival of cancer cells.19 The EGFR ENPEP protein is overabundant in ~40%C80% of NSCLC tumors.20 Initially, investigators believed that gefitinib may completely terminate EGFR activity, which takes on a pivotal part in the management of cellular growth and proliferation. However, the medical trials were disappointing because tumor response was not corresponding to the amount of EGFR.21 In June 2004, experts at Harvard Medical School 1st reported that specific mutations in the TK website of the gene may be the necessary precondition of clinical responsiveness to the TKI.22 Analysis showed the response to gefitinib was 80% in tumors with positive mutations in the TK website of the gene. On the contrary, little effect was found in tumors with bad mutations. Once published, these significant study findings produced high attention from scholars all over the world and were continually identified in the USA, Japan, Korean, and the Peoples Republic of China after 1 year. Experts from Taiwan 1st illustrated the association between EGFR mutation status of tumors and the responsiveness to gefitinib in Chinese people. PKA inhibitor fragment (6-22) amide Among the 16 individuals treated with gefitinib, seven of nine who responded experienced EGFR mutations, while only one of seven who failed to respond experienced EGFR mutations. The difference in mutation rates between the responders and nonresponders was statistically significant (gene is composed of 28 exons, and the entire TK domain is definitely encoded by exons 18C24. So far, ~90% of gene mutations were found out in exons 19C21. Specific mutations in NSCLC.24 Other gene mutations, the difference between the Peoples Republic of China and the world advanced level was only 6 months because of the research directed by Taiwan experts.23 A related article from mainland China was published in March 2005 that identified ten somatic mutations from a total of 41 lung malignancy individuals in the Peoples Republic of China.26 Similar to the effect analysis of overseas data, eight of these mutations are deletions in exon 19, one point mutation in exon 21, and one deletion/insertion in exon 20. Based on the data of 76 lung malignancy individuals from mainland China completed by Beijing Union Medical College investigators, a research on the detection of gene mutation 1st showed that there was a distinct correlation between mutation conditions and responsiveness to gefitinib in mainland Chinese individuals with NSCLC.27 Pharmacokinetics Gefitinib is an anilinoquinazoline compound with the chemical name of 4-quinazolinamine, mutation-positive tumors. Phase I trials possess identified that the optimal dose range of security is definitely 250C500 mg/d that has been confirmed by dose escalation security/tolerability trials. Studies have shown that 250 mg/d was the PKA inhibitor fragment (6-22) amide PKA inhibitor fragment (6-22) amide minimum amount concentration for effective.