Imatinib nilotinib resistance mutations

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.

Nilotinib and dasatinib both emerged into clinical use after the experience of imatinib resistant clinical mutations had been identified and characterized. 

Unfortunately, the T3151 mutation poses a formidable therapeutic challenge as it mediates complete resistance not only to imatinib, but also to many of the next generation of ABL kinase inhibitors, including both dasatinib and nilotinib. Efforts to find compounds that overcome the issues caused by... 

---