title: Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy.
abstract: The acquisition of mutations within the BCR-ABL1 kinase domain is frequently associated with tyrosine kinase inhibitor (TKI) failure in chronic myeloid leukemia. Sensitive sequencing techniques have revealed a high prevalence of compound BCR-ABL1 mutations (polymutants) in patients failing TKI therapy. To investigate the molecular consequences of such complex mutant proteins with regards to TKI resistance, we determined by cloning techniques the presence of polymutants in a cohort of chronic-phase patients receiving imatinib followed by dasatinib therapy. The analysis revealed a high frequency of polymutant BCR-ABL1 alleles even after failure of frontline imatinib, and also the progressive exhaustion of the pool of unmutated BCR-ABL1 alleles over the course of sequential TKI therapy. Molecular dynamics analyses of the most frequent polymutants in complex with TKIs revealed the basis of TKI resistance. Modeling of BCR-ABL1 in complex with the potent pan-BCR-ABL1 TKI ponatinib highlighted potentially effective therapeutic strategies for patients carrying these recalcitrant and complex BCR-ABL1 mutant proteins while unveiling unique mechanisms of escape to ponatinib therapy.
authors.affiliation: Department of Thoracic, Head/Neck Medical Oncology and Department of Molecular and Cellular Oncology, MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.forename: Paola
authors.initials: P
authors.lastname: Posocco
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fermeglia
authors.forename: Hanshi
authors.initials: H
authors.lastname: Sun
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.forename: Nicholas
authors.initials: N
authors.lastname: Donato
authors.forename: Alfonso
authors.initials: A
authors.lastname: Quintás-Cardama
mesh_terms: D000704:Analysis of Variance; D001549:Benzamides; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D010879:Piperazines; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines
chemical_list: D001549:Benzamides; D017931:DNA Primers; D007093:Imidazoles; D010879:Piperazines; D011724:Pyridazines; D011743:Pyrimidines; C545373:ponatinib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl
keywords: compound mutation; ponatinib resistance