Mechanistically distinct classes of BCR::ABL1 mutations confer resistance to asciminib.

Asciminib resistance in chronic myeloid leukemia is split into two mechanistically distinct BCR::ABL1 mutation classes, with class I reducing drug affinity up to 90-fold.

• Why it matters: Secondary resistance to the allosteric inhibitor asciminib is not fully explained at the molecular level, limiting resistance monitoring and rational therapy planning in CML.
• What they did: Clinically observed resistance mutations were analyzed using structural modeling, HDX-MS, quantitative biochemical assays, and molecular dynamics simulations to test how each mutation affects asciminib binding and kinase regulation.
• The result: Class I mutations impair asciminib binding via steric effects, while class II mutations (including F359I and M244V) retain wildtype binding affinity but increase intrinsic kinase activity and autophosphorylation by disrupting the drug-induced autoinhibited conformation.

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