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. Author manuscript; available in PMC: 2011 Mar 1.
Published in final edited form as: Biochim Biophys Acta. 2009 Dec 22;1804(3):559–566. doi: 10.1016/j.bbapap.2009.12.010

Figure 5. The increased ATP affinity of the L858R/T790M mutant leads to gefitinib resistance at cellular concentrations of ATP.

Figure 5

A, The calculated potency (Kiapp) of gefitinib for the L858R and L858R/T790M mutants is plotted versus ATP concentration according to the equation Kiapp=Ki (1 + [S]/Km[ATP]), where [S] is the concentration of ATP. We set Ki = Kd as measured in our direct binding assays (see text). The drug resistant mutant is expected to lose potency as ATP concentrations approach the ~1 mM level found in the cell. B and C, experimental inhibition curves for the L858R and L858R/T790M mutants, respectively. The in vitro kinase activity of each mutant was measured in the presence of the indicated concentration of gefitinib at either 0.01 mM ATP (black squares) or 1.0 mM ATP (grey circles). The vertical arrows indicate the approximate serum concentration of gefitinib (~ 1µM) that is achievable in patients. (Figure adapted from Yun et al. [17])