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 B...

Autores
Mian, Afsar Ali; Haberbosch, Isabella; Khamaisie, Hazem; Agbarya, Abed; Pietsch, Larissa; Eshel, Elizabeh; Najib, Dally; Chiriches, Claudia; Ottmann, Oliver Gerhard; Hantschel, Oliver; Biondi, Ricardo Miguel; Ruthardt, Martin; Mahajna, Jamal
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Mian, Afsar Ali. Cardiff University; Reino Unido. The Aga Khan University; Pakistán
Fil: Haberbosch, Isabella. Goethe Universitat Frankfurt; Alemania
Fil: Khamaisie, Hazem. Migal Galilee Technology Center Israel; Israel
Fil: Agbarya, Abed. Centre Médical Bnai Zion; Israel
Fil: Pietsch, Larissa. Goethe Universitat Frankfurt; Alemania. German Cancer Consortium; Alemania
Fil: Eshel, Elizabeh. Bar Ilan University; Israel
Fil: Najib, Dally. Bar Ilan University; Israel
Fil: Chiriches, Claudia. Cardiff University; Reino Unido
Fil: Ottmann, Oliver Gerhard. Cardiff University; Reino Unido
Fil: Hantschel, Oliver. École Polytechnique Fédérale de Lausanne; Suiza. Universitat Phillips; Alemania
Fil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Goethe Universitat Frankfurt; Alemania. German Cancer Consortium; Alemania
Fil: Ruthardt, Martin. Cardiff University; Reino Unido
Fil: Mahajna, Jamal. Migal Galilee Technology Center Israel; Israel. Tel Hai Academic College; Israel
Materia
ALLOSTERIC INHIBITION
BCR-ABL1
COMPOUND MUTATIONS
CRIZOTINIB
PHILADELPHIA CHROMOSOME–POSITIVE LEUKEMIA
TKI RESISTANCE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/184498
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/184498
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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-E255KMian, Afsar AliHaberbosch, IsabellaKhamaisie, HazemAgbarya, AbedPietsch, LarissaEshel, ElizabehNajib, DallyChiriches, ClaudiaOttmann, Oliver GerhardHantschel, OliverBiondi, Ricardo MiguelRuthardt, MartinMahajna, JamalALLOSTERIC INHIBITIONBCR-ABL1COMPOUND MUTATIONSCRIZOTINIBPHILADELPHIA CHROMOSOME–POSITIVE LEUKEMIATKI RESISTANCEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Resistance 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.Fil: Mian, Afsar Ali. Cardiff University; Reino Unido. The Aga Khan University; PakistánFil: Haberbosch, Isabella. Goethe Universitat Frankfurt; AlemaniaFil: Khamaisie, Hazem. Migal Galilee Technology Center Israel; IsraelFil: Agbarya, Abed. Centre Médical Bnai Zion; IsraelFil: Pietsch, Larissa. Goethe Universitat Frankfurt; Alemania. German Cancer Consortium; AlemaniaFil: Eshel, Elizabeh. Bar Ilan University; IsraelFil: Najib, Dally. Bar Ilan University; IsraelFil: Chiriches, Claudia. Cardiff University; Reino UnidoFil: Ottmann, Oliver Gerhard. Cardiff University; Reino UnidoFil: Hantschel, Oliver. École Polytechnique Fédérale de Lausanne; Suiza. Universitat Phillips; AlemaniaFil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Goethe Universitat Frankfurt; Alemania. German Cancer Consortium; AlemaniaFil: Ruthardt, Martin. Cardiff University; Reino UnidoFil: Mahajna, Jamal. Migal Galilee Technology Center Israel; Israel. Tel Hai Academic College; IsraelSpringer2021-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/184498Mian, Afsar Ali; Haberbosch, Isabella; Khamaisie, Hazem; Agbarya, Abed; Pietsch, Larissa; et al.; 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; Springer; Annals of Hematology; 100; 8; 6-2021; 2023-20290939-5555CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://link.springer.com/article/10.1007/s00277-020-04357-zinfo:eu-repo/semantics/altIdentifier/doi/10.1007/s00277-020-04357-zinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-04-15T10:18:35Zoai:ri.conicet.gov.ar:11336/184498instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-04-15 10:18:36.304CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv 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
title 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
spellingShingle 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
ALLOSTERIC INHIBITION
BCR-ABL1
COMPOUND MUTATIONS
CRIZOTINIB
PHILADELPHIA CHROMOSOME–POSITIVE LEUKEMIA
TKI RESISTANCE
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
dc.creator.none.fl_str_mv Mian, Afsar Ali
Haberbosch, Isabella
Khamaisie, Hazem
Agbarya, Abed
Pietsch, Larissa
Eshel, Elizabeh
Najib, Dally
Chiriches, Claudia
Ottmann, Oliver Gerhard
Hantschel, Oliver
Biondi, Ricardo Miguel
Ruthardt, Martin
Mahajna, Jamal
author Mian, Afsar Ali
author_facet Mian, Afsar Ali
Haberbosch, Isabella
Khamaisie, Hazem
Agbarya, Abed
Pietsch, Larissa
Eshel, Elizabeh
Najib, Dally
Chiriches, Claudia
Ottmann, Oliver Gerhard
Hantschel, Oliver
Biondi, Ricardo Miguel
Ruthardt, Martin
Mahajna, Jamal
author_role author
author2 Haberbosch, Isabella
Khamaisie, Hazem
Agbarya, Abed
Pietsch, Larissa
Eshel, Elizabeh
Najib, Dally
Chiriches, Claudia
Ottmann, Oliver Gerhard
Hantschel, Oliver
Biondi, Ricardo Miguel
Ruthardt, Martin
Mahajna, Jamal
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ALLOSTERIC INHIBITION
BCR-ABL1
COMPOUND MUTATIONS
CRIZOTINIB
PHILADELPHIA CHROMOSOME–POSITIVE LEUKEMIA
TKI RESISTANCE
topic ALLOSTERIC INHIBITION
BCR-ABL1
COMPOUND MUTATIONS
CRIZOTINIB
PHILADELPHIA CHROMOSOME–POSITIVE LEUKEMIA
TKI RESISTANCE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Mian, Afsar Ali. Cardiff University; Reino Unido. The Aga Khan University; Pakistán
Fil: Haberbosch, Isabella. Goethe Universitat Frankfurt; Alemania
Fil: Khamaisie, Hazem. Migal Galilee Technology Center Israel; Israel
Fil: Agbarya, Abed. Centre Médical Bnai Zion; Israel
Fil: Pietsch, Larissa. Goethe Universitat Frankfurt; Alemania. German Cancer Consortium; Alemania
Fil: Eshel, Elizabeh. Bar Ilan University; Israel
Fil: Najib, Dally. Bar Ilan University; Israel
Fil: Chiriches, Claudia. Cardiff University; Reino Unido
Fil: Ottmann, Oliver Gerhard. Cardiff University; Reino Unido
Fil: Hantschel, Oliver. École Polytechnique Fédérale de Lausanne; Suiza. Universitat Phillips; Alemania
Fil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Goethe Universitat Frankfurt; Alemania. German Cancer Consortium; Alemania
Fil: Ruthardt, Martin. Cardiff University; Reino Unido
Fil: Mahajna, Jamal. Migal Galilee Technology Center Israel; Israel. Tel Hai Academic College; Israel
description 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.
publishDate 2021
dc.date.none.fl_str_mv 2021-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/184498
Mian, Afsar Ali; Haberbosch, Isabella; Khamaisie, Hazem; Agbarya, Abed; Pietsch, Larissa; et al.; 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; Springer; Annals of Hematology; 100; 8; 6-2021; 2023-2029
0939-5555
CONICET Digital
CONICET
url http://hdl.handle.net/11336/184498
identifier_str_mv Mian, Afsar Ali; Haberbosch, Isabella; Khamaisie, Hazem; Agbarya, Abed; Pietsch, Larissa; et al.; 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; Springer; Annals of Hematology; 100; 8; 6-2021; 2023-2029
0939-5555
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://link.springer.com/article/10.1007/s00277-020-04357-z
info:eu-repo/semantics/altIdentifier/doi/10.1007/s00277-020-04357-z
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.203462

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