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, Ottmann, Oliver, Hantschel, Oliver, Biondi, Ricardo M., Ruthardt, Martin 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:	29 Mar 2022 10:18
URI:	https://orca.cardiff.ac.uk/id/eprint/136955

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