Many cancer drugs have been de
Many cancer drugs have been developed that inhibit or activateenzyme function.
a. Geftinib is a tyrosine kinase inhibitor that has been shownto specifically target EGFR. EGFR is a receptor tyrosinekinase (RTK) and can become constitutively activein a cancer cell. Before we continue, explain how a RTKsfunction to transmit a signal (EGF) from the outside of the cellacross the membrane to the inside of the cell. Be specific, whatchanges occur on the outside of the cell when ligand is bound? Whatchanges occur on the inside of the cell that pass that informationfrom the receptor to the first downstream target? I don’t need theentire signal transduction cascade. Rubric (4): correctexplanation with the effect of ligand binding by the receptor onoutside of the cell (2) and effect of ligand binding on inside ofthe cell (2).
b. Geftinib has been shown to occupy the ATP binding site of thetyrosine kinase domain of the EGFR, therefore we can hypothesizethat it acts as a(n) __________________ inhibitor.(2pts)
c. Let’s think about a specific mutation in the EGFR(L858R). The Kd for ATP binding to thetyrosine kinase domain of the EGFR (L858R) mutation is 148mM whilethe Kd of Geftinib for the L858R mutation of the EGFR is 2.4nM.Which binds more tightly (ATP or Geftinib) to EGFR (L858R) and howdo these numbers confirm your conclusion in “b”? Rubric(4): correct analysis of binding (2) and correct explanation thatrelates analysis to conclusion in “b” (2).
d. Researchers determined proteins downstream of activated EGFRthat were affected by Geftinib. We know some of these proteins! Inthe experiment, cancer cells with constitutively active EGFR aretreated with or without Geftinib. In these experiments, Raf wasdownregulated in the cells treated with Geftinib when compared tountreated. Why does this make sense? Make sure yousubstantiate your answer with concepts covered this week!Rubric (4): correct correlation is made between specificeffect of the drug (1) and obvious application of concepts taughtthis week is applied to the answer, and they are correct(3).
Answer:
a.
Extracellular ligand binding will cause or stabilize receptordimerization. This allows a tyrosine in the cytoplasmic domain ofthe receptor monomer to be trans phosphorylated by the otherreceptor by which the signal is transmitted into the cell. Theactivation of the receptor will induce the binding of Src homology2 domain and PTB domain containing proteins. This will lead toinitiation of signal transduction inside the cell.
b. By binding to the EGFR receptor tyrosine kinase domain, itacts as a EGFR inhibitor.
c. Kd the equilibrium dissociation constant between the receptorand a substrate. Kd and affinity are inversely related. So lowerthe Kd value and thus the higher affinity for the substrate towardsthe receptor. According to the values, Geftinib has concentrationin nM range which will lead to higher affinity to the EGFR mutationcompared to the ATP.
d. The main action of EGFR mutation is through constitutiveactivation of Raf, while in the cells treated with Geftinib havedownregulated Raf which means that mode of action of Geftinib is byreducing the activation of Raf in the cells.
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