actor receptor Egfr of the epidermal growth factor and in Kras of the Raf/Mek/Erk signaling pathway, respectively. Mutations in Egfr remove an autoinhibitory effect, lead to increased phosphorylation and to ligand-independent dimerization of the receptor. Mutations that render the receptor constitutively active also confer higher affinity for drugs such as gefitinib or erlotinib. Known as tyrosine kinase inhibitors (TKI), the drugs compete with ATP for binding to the tyrosine kinase pocket of Egfr (other drugs include monoclonal antibodies that target the ligand binding domain and compete with the endogenous ligands). The efficiency of TKI is however lost within one year of treatment due to acquired resistance. Secondary mutations in Egfr, such as the T790M substitution reported in ~50% of cases and amplification of Met receptor observed in ~20% of cases are thought to be contributing factors. T790M mutation lies within the ATP binding site and is thought to interfere with drug binding; Met amplification appears to involve activation of Erbb3. Note that Egfr and Met mediated signaling activate PI3K-Akt pathway; within the Egf context, Erbb3 is the main effector while under normal conditions Met does not engage Egfr members. Mutations in Kras lead to irreversible GTP binding resulting in its constitutive activation. Other culprits include Erbb2, Pik3ca, Akt1, Braf and Map2k1. Like Egfr, Erbb2 is a receptor for epidermal growth whose NSCLC associated mutations give rise to a constitutively active receptor. Mutations in Pik3ca, the catalytic subunit of class IA lipid kinase PI3K, and in the Akt1member of the AKT kinase family lead to gain of function. Mutant Pik3ca leads to Akt activation in the absence of growth factor stimulation, the activity of mutant Akt1 is independent of upstream PI3K function. Mutations in Braf lead to increased kinase activity while Map2k1, downstream of Braf shows gain of function in vitro in these members of the Raf/Mek/Erk cascade. At the same time, mutations in known tumor suppressors such as Tp53 or Pten lead to loss of activity thus abrogating their tumor suppressor capacity. In addition to the TKIs mentioned, other drugs are being developed that target these and other mutants associated with NSCLC and mentioned in the text. NSCLC is one of the tumor types for which platinum (Pt)-containing drugs such as cisplatin are used as chemotherapy agents. To see the ontology report for annotations GViewer and download, click here
To see the Disease Ontology report for genes that in some fashion have been associated with NSCLC or suspected to confer susceptibility, click here
To link to the Cancer Disease Portal, click here
To link to the Respiratory Disease Portal, click here
[click to see the associated KEGG map - map05223]...(less)