Revisiting Asciminib Resistance: From Binding Affinity to Allosteric Disruption in BCR::ABL1 Leukemias.

Tyrosine kinase inhibitors (TKIs) have reshaped the treatment of BCR::ABL1 positive leukemias. The first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, asciminib introduces a distinct therapeutic paradigm by targeting the myristoyl pocket and avoids direct competition with ATP. However, resistance to asciminib has been reported in 4-10% of chronic myeloid leukemia (CML) cases. Asciminib resistance is predominantly driven by impaired allosteric regulations: 1) Expanded spectrum of kinase domain mutations "pre-activate" the kinase and confer resistance despite retained drug affinity; 2) Intrinsic primary resistance, from b2(e13)a3 and b3(e14)a3 transcript variants; and 3) Isoform-specific (p190 vs. p210) resistance, with common Ploop mutations exhibit greater resistance in p190 than in p210. This paradigm shift from an "affinity" problem to an "allostery" problem necessitates a corresponding evolution in clinical and laboratory practice. This includes expanding mutational screening, incorporating pre-treatment screening of the BCR::ABL1 isoforms, and transcript types to appropriately guide therapeutic selection.