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

Mian, Afsar Ali, Haberbosch, Isabella, Khamaisie, Hazem, Agbarya, Abed, Pietsch, Larissa, Eshel, Elizabeh, Najib, Dally, Chiriches, Claudia ORCID: https://orcid.org/0000-0003-3758-1892, Ottmann, Oliver ORCID: https://orcid.org/0000-0001-9559-1330, Hantschel, Oliver, Biondi, Ricardo M., Ruthardt, Martin ORCID: https://orcid.org/0000-0003-1021-3811 and Mahajna, Jamal 2021. 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. Annals of Hematology 100 , pp. 2023-2029. 10.1007/s00277-020-04357-z

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Springer Verlag (Germany)
ISSN:	0939-5555
Date of First Compliant Deposit:	11 December 2020
Date of Acceptance:	17 November 2020
Last Modified:	27 Oct 2023 06:17
URI:	https://orca.cardiff.ac.uk/id/eprint/136955

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