l cell lung cancer (NSCLC). NSCLC is a major cause of cancer mortality accounting for ~80% of all cases, the remaining 20% being attributable to the small-cell lung cancer type (SCLC). Mutations in Egfr are among several well documented contributors to non-small cell lung cancer (NSCLC). They remove an autoinhibitory effect and lead to increase activity even in the absence of ligand binding. Mutations that render the receptor constitutively active also confer higher affinity for the TKI drugs. Gefitinib is primarily metabolized by CYP3A4 and also by CYP3A5, CYP2D6 and the extrahepatic CYP1A1. The drug has been shown to inhibit the activity of CYP2C19 as well as CYP2D6 but the clinical relevance of these findings is however questioned. Several metabolites are being produced; O-desmethyl-derivative (M523595) appears to be the main one resulting from CYP2D6 activity. The CYP enzymes involved in the metabolism of gefitinib and erlotinib have been characterized in human liver and intestinal microsomes (the human genes are shown). Gefitinib and metabolites are disposed off through the action of ABCG2 and to a lesser extent ABCB1 human efflux transporters (human genes are shown). Gefitinib metabolism has also been shown in rats and dogs but the identity of the enzymes involved remains to be established. It is of note that the drug appears to be extensively metabolized by rats, followed by dogs and humans and that the metabolites produced are more similar between dogs and human than between either species and rat. Polymorphism in CYP3A4, CYP3A5 and CYP2D6 has been reported; for CYP3A5 and CYP2D6 it can have serious consequences for drug metabolism, particularly in Caucasians. The efficiency of gefitinib and other TKI is lost within one year of treatment due to acquired resistance. Secondary mutations in Egfr interfere with TKI binding and promote constitutive activation. In addition, amplification of Met oncogene which normally does not engage Egfr members, also leads to increased activation of the receptor and appears to involve Erbb3. Met amplification can lead to increased activation of downstream signaling pathways independent of Egfr; both Egfr and Met mediated signaling impinge upon the same intracellular cascades. The eventually acquired resistance to TKI and the involvement of other altered pathways in NSCLC, has prompted the development of other drugs for the treatment of the disease, including second generation TKI. To see the ontology report for annotations, GViewer and download, click here.
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