Polymutant BCR-ABL1 proteins during chronic myeloid leukemia therapy: novel mechanisms of resistance from clinical, in vitro, and in silico evidences

The acquisition of mutations within the BCR-ABL1 kinase domain is frequently associated with imatinib failure among patients with chronic myeloid leukemia. Typically, patients failing imatinib undergo sequential therapy with second line tyrosine kinase inhibitors (TKIs) such as nilotinib or dasatinib. To investigate the prevalence of BCR-ABL1 mutations and the mechanisms of acquired TKI resistance during sequential therapy, we utilized a sensitive cloning technique in a cohort of chronic-phase patients failing imatinib therapy that subsequently received dasatinib. The analysis revealed that most patients failing imatinib carry BCR-ABL1 mutations, many with polymutant BCR-ABL1 alleles, and that there is progressive exhaustion of the pool of unmutated BCR-ABL1 alleles over the course of treatment. In silico modeling of the most frequent polymutants demonstrated profound resistance to imatinib and second line TKIs. Modeling of BCR-ABL1 in complex with the recently approved TKI ponatinib highlighted potentially effective therapeutic strategies for patients carrying these recalcitrant and complex BCR-ABL1 mutant proteins while unveiling novel mechanisms of escape to ponatinib therapy.