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

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 l...

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Bibliographic Details
Published in:Cancer cell 2019-10, Vol.36 (4), p.431-443.e5
Main Authors: Eide, Christopher A., Zabriskie, Matthew S., Savage Stevens, Samantha L., Antelope, Orlando, Vellore, Nadeem A., Than, Hein, Schultz, Anna Reister, Clair, Phillip, Bowler, Amber D., Pomicter, Anthony D., Yan, Dongqing, Senina, Anna V., Qiang, Wang, Kelley, Todd W., Szankasi, Philippe, Heinrich, Michael C., Tyner, Jeffrey W., Rea, Delphine, Cayuela, Jean-Michel, Kim, Dong-Wook, Tognon, Cristina E., O'Hare, Thomas, Druker, Brian J., Deininger, Michael W.
Format: Article
Language:English
Subjects:
ABL001
allosteric inhibitors
Allosteric Regulation - drug effects
Animals
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
asciminib
Binding Sites - drug effects
Binding Sites - genetics
Cell Line, Tumor - transplantation
chronic myeloid leukemia
compound mutation
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
ponatinib
Primary Cell Culture
Pyrazoles - pharmacology
Pyrazoles - therapeutic use
Pyridazines - pharmacology
Pyridazines - therapeutic use
targeted therapy
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Summary: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. •Most BCR-ABL1 point mutants but not compound mutants are sensitive to asciminib•Variants at BCR-ABL1 position F359 are linked with asciminib resistance in patients•Combination of asciminib with ponatinib restores efficacy against compound mutants Most clinical BCR-ABL1 compound mutants are insensitive to current clinical tyrosine kinase inhibitors. Eide et al. show that adding asciminib, an allosteric inhibitor, to ponatinib, an ATP site inhibitor, effectively targets compound mutants and provides a potential mechanism for the collaborative effect.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2019.08.004