Cancer Cell
Volume 36, Issue 4, 14 October 2019, Pages 431-443.e5
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Article
Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants

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Highlights

  • 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

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.

Keywords

asciminib
ABL001
allosteric inhibitors
chronic myeloid leukemia
ponatinib
targeted therapy
compound mutation

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