Crizotinib acts as ABL1 inhibitor combining ATP-binding with allosteric inhibition and is active against native BCR-ABL1 and its resistance and compound mutants BCR-ABL1T315I and BCR-ABL1T315I-E255K

Afsar Ali Mian, Isabella Haberbosch, Hazem Khamaisie, Abed Agbarya, Larissa Pietsch, Elizabeh Eshel, Dally Najib, Claudia Chiriches, Oliver Gerhard Ottmann, Oliver Hantschel, Ricardo M. Biondi, Martin Ruthardt, Jamal Mahajna

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Resistance remains the major clinical challenge for the therapy of Philadelphia chromosome–positive (Ph+) leukemia. With the exception of ponatinib, all approved tyrosine kinase inhibitors (TKIs) are unable to inhibit the common “gatekeeper” mutation T315I. Here we investigated the therapeutic potential of crizotinib, a TKI approved for targeting ALK and ROS1 in non-small cell lung cancer patients, which inhibited also the ABL1 kinase in cell-free systems, for the treatment of advanced and therapy-resistant Ph+ leukemia. By inhibiting the BCR-ABL1 kinase, crizotinib efficiently suppressed growth of Ph+ cells without affecting growth of Ph− cells. It was also active in Ph+ patient-derived long-term cultures (PD-LTCs) independently of the responsiveness/resistance to other TKIs. The efficacy of crizotinib was confirmed in vivo in syngeneic mouse models of BCR-ABL1- or BCR-ABL1T315I-driven chronic myeloid leukemia–like disease and in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). Although crizotinib binds to the ATP-binding site, it also allosterically affected the myristol binding pocket, the binding site of GNF2 and asciminib (former ABL001). Therefore, crizotinib has a seemingly unique double mechanism of action, on the ATP-binding site and on the myristoylation binding pocket. These findings strongly suggest the clinical evaluation of crizotinib for the treatment of advanced and therapy-resistant Ph+ leukemia.

Original languageEnglish
Pages (from-to)2023-2029
Number of pages7
JournalAnnals of Hematology
Volume100
Issue number8
DOIs
StatePublished - Aug 2021

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

Funding

Dr. Hantschel reports receiving consulting fees from Intima Biosciences Inc. Dr. Ottmann reports receiving honoraria for AdBoards from Pfizer, Novartis, Celgene, Amgen, Incyte, Takeda, Roche, Fusion Pharma, and Sun Pharma. His research is supported by Incyte, Amgen, and Celgene. Dr. Ruthardt reports having received honoraria from Novartis, Fusion Pharma, and Sun Pharma and his research was supported by Fusion Pharma and Sun Pharma.

FundersFunder number
Fusion Pharma
Incyte
Amgen
Novartis
Celgene
Cardiff University
School of Psychology, Cardiff University
School of Chemistry, Cardiff University

    Keywords

    • Allosteric inhibition
    • BCR-ABL1
    • Compound mutations
    • Crizotinib
    • Philadelphia chromosome–positive leukemia
    • TKI resistance

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