Resistance Mutations Kinase

Yamamoto M, Kurosu T, Kakihana K et al. The two major imatinib resistance mutations, E255K and T3151, enhance the activity of BCR/ABL fusion kinase. Biochem Biophys Res Commun 2004 319 1272-1275. 

This dynamic multidrug-targeted prevention technique has been proposed in the treatment of chronic myeloid leukemia and the positive results obtained with the newly introduced drugs nilotinib and dasatinib suggested that a combination of two or three kinase inhibitors, when carefully selected to cover all known resistant mutations, could shut off all mechanisms of escape. 

It is difficult to deconvolute how kinase inhibitor binding mode has implications in the clinic. In general, selectivity tends to increase in the order (i) purine site, (ii) selectivity pocket, and (iii) allosteric site. The ability to overcome resistance mutations in cancer therapy tends to be inversely related to this selectivity pattern. Accordingly, allosteric kinase inhibition may become a preferred mechanism for clinical indications other than cancer. 

In the following sections, the cancers relevant to kinases inhibited by imatinib will be reviewed. Clinical resistance mutations will be described, most of which were identified based on the clinical experience with imatinib. The development of the two second-generation inhibitors will be described, and subsequent clinical experience will be reviewed. Finally, additional kinase inhibitors to this group of kinases will be reviewed. 

Of the resistance mutations, these are believed to act by two mechanisms. Some of these mutations occur at inward-facing residues of the ATP binding site, which also binds the inhibitor. In this case, a significant decrease in inhibitor binding potency occurs, but the binding of ATP tolerates the mutated residue. The second effect of resistance mutations is to shift the equilibrium of the kinase to its active form. Since imatinib binds to the inactive form of the kinase, this will reduce the availability of its binding state. 

Figure 5.2 Sequences of important regions of Abl kinase, highlighting sites of resistance mutations identified from clinical tumor samples. Several mutations including Y253F-H, E255 K-V, and T315I have a > 10-fold impact on imatinib potency when tested in a Ba-F3 cellular proliferation assay.31 Only T315I retains such a significant resistance effect on the second generation inhibitors dasatinib and nilotinib.

Resistance mutations to imatinib and successor compounds (KIT kinase)... 

Given the convergence between the resistance mutations found in cancer and the mutations used to engineer orthogonal kinase ligands, it is reasonable... 

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