Fig. 2 Asciminib resistance hotspots in ABL1 kinase domain

Figure 2 illustrates the results of deep mutational scanning (DMS) used to map asciminib resistance hotspots specifically within the ABL1 kinase domain. The comprehensive heatmap and accompanying structural models confirm that known clinical mutations, such as M244V and V468F, drive strong resistance. Furthermore, the figure maps out numerous novel, highly resistant variants concentrated around the myristoyl binding pocket and the alpha-I'-helix (including sites F497, I502, V506, and L510). Notably, the data highlights potent new resistance mutations like E505G, K294E, and D276G, as well as an "proline resistance band" that disrupts the alpha-I-helix structure required for asciminib inhibition. Finally, the functional growth rate assays confirm that cells harboring these specific mutations continue to thrive even at high concentrations of asciminib.