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-$ ABL1^{T315I} $ and BCR-$ ABL1^{T315I-E255K} $
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-$ ABL1^{T315I} $-driven chronic myeloid leukemia–like disease and in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). Although crizotinib binds to the ATP-binding site, it also allosterically affected the myristol binding pocket, the binding site of GNF2 and asciminib (former ABL001). Therefore, crizotinib has a seemingly unique double mechanism of action, on the ATP-binding site and on the myristoylation binding pocket. These findings strongly suggest the clinical evaluation of crizotinib for the treatment of advanced and therapy-resistant Ph+ leukemia..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:100 |
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| Enthalten in: |
Annals of hematology - 100(2021), 8 vom: 10. Juni, Seite 2023-2029 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mian, Afsar Ali [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
Allosteric inhibition |
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| Anmerkungen: |
© The Author(s) 2020 |
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| doi: |
10.1007/s00277-020-04357-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
OLC2126668207 |
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| 245 | 1 | 0 | |a Crizotinib acts as ABL1 inhibitor combining ATP-binding with allosteric inhibition and is active against native BCR-ABL1 and its resistance and compound mutants BCR-$ ABL1^{T315I} $ and BCR-$ ABL1^{T315I-E255K} $ |
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| 520 | |a 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-$ ABL1^{T315I} $-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. | ||
| 650 | 4 | |a Crizotinib | |
| 650 | 4 | |a Philadelphia chromosome–positive leukemia | |
| 650 | 4 | |a BCR-ABL1 | |
| 650 | 4 | |a TKI resistance | |
| 650 | 4 | |a Allosteric inhibition | |
| 650 | 4 | |a Compound mutations | |
| 700 | 1 | |a Haberbosch, Isabella |4 aut | |
| 700 | 1 | |a Khamaisie, Hazem |4 aut | |
| 700 | 1 | |a Agbarya, Abed |4 aut | |
| 700 | 1 | |a Pietsch, Larissa |4 aut | |
| 700 | 1 | |a Eshel, Elizabeh |4 aut | |
| 700 | 1 | |a Najib, Dally |4 aut | |
| 700 | 1 | |a Chiriches, Claudia |4 aut | |
| 700 | 1 | |a Ottmann, Oliver Gerhard |4 aut | |
| 700 | 1 | |a Hantschel, Oliver |4 aut | |
| 700 | 1 | |a Biondi, Ricardo M. |4 aut | |
| 700 | 1 | |a Ruthardt, Martin |0 (orcid)0000-0003-1021-3811 |4 aut | |
| 700 | 1 | |a Mahajna, Jamal |4 aut | |
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