Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants

Cancer Cell. 2019 Oct 14;36(4):431-443.e5. doi: 10.1016/j.ccell.2019.08.004. Epub 2019 Sep 19.

Abstract

BCR-ABL1 point mutation-mediated resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) leukemia is effectively managed with several approved drugs, including ponatinib for BCR-ABL1T315I-mutant disease. However, therapy options are limited for patients with leukemic clones bearing multiple BCR-ABL1 mutations. Asciminib, an allosteric inhibitor targeting the myristoyl-binding pocket of BCR-ABL1, is active against most single mutants but ineffective against all tested compound mutants. We demonstrate that combining asciminib with ATP site TKIs enhances target inhibition and suppression of resistant outgrowth in Ph+ clinical isolates and cell lines. Inclusion of asciminib restores ponatinib's effectiveness against currently untreatable compound mutants at clinically achievable concentrations. Our findings support combining asciminib with ponatinib as a treatment strategy for this molecularly defined group of patients.

Keywords: ABL001; allosteric inhibitors; asciminib; chronic myeloid leukemia; compound mutation; ponatinib; targeted therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Binding Sites / drug effects
  • Binding Sites / genetics
  • Cell Line, Tumor / transplantation
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • Imidazoles / pharmacology*
  • Imidazoles / therapeutic use
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Targeted Therapy / methods
  • Mutation
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Niacinamide / therapeutic use
  • Primary Cell Culture
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Pyridazines / pharmacology*
  • Pyridazines / therapeutic use

Substances

  • BCR-ABL1 fusion protein, human
  • Imidazoles
  • Pyrazoles
  • Pyridazines
  • asciminib
  • Niacinamide
  • ponatinib
  • Fusion Proteins, bcr-abl