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.

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.

• Authors: 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
• Journal: Annals of hematology (Ann Hematol) Vol. 100 Issue 8 Pg. 2023-2029 (Aug 2021) ISSN: 1432-0584 [Electronic] Germany
• PMID: 34110462 (Publication Type: Journal Article)
• Copyright: © 2020. The Author(s).

Chemical References

• Antineoplastic Agents
• BCR-ABL1 fusion protein, human
• Protein Kinase Inhibitors
• Crizotinib
• Adenosine Triphosphate
• ABL1 protein, human
• Fusion Proteins, bcr-abl
• Proto-Oncogene Proteins c-abl

Topics

• Adenosine Triphosphate (metabolism)
• Allosteric Regulation (drug effects)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Crizotinib (pharmacology)
• Drug Resistance, Neoplasm
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics, metabolism)
• Humans
• Jurkat Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism)
• Mice
• Mutation (drug effects)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-abl (antagonists & inhibitors, metabolism)