Dasatinib induces endothelial dysfunction leading to impaired recovery from ischaemia

Ayala Gover-Proaktor; Dorit Leshem-Lev; Sabina Winograd-Katz; Shirly Partouche; Aladin Samara; Saar Shapira; Inbar Nardi-Agmon; Emanuel Harari; Aseel Younis; Abderrahman Najjar; Ran Kornowski; Benjamin Geiger; Pia Raanani; Avi Leader; Galit Granot

doi:10.1111/bjh.19595

Dasatinib induces endothelial dysfunction leading to impaired recovery from ischaemia

Ayala Gover-Proaktor, Dorit Leshem-Lev, Sabina Winograd-Katz, Shirly Partouche, Aladin Samara, Saar Shapira, Inbar Nardi-Agmon, Emanuel Harari, Aseel Younis, Abderrahman Najjar, Ran Kornowski, Benjamin Geiger, Pia Raanani, Avi Leader, Galit Granot^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Chronic myeloid leukaemia (CML) management is complicated by treatment-emergent vascular adverse events seen with tyrosine kinase inhibitors (TKIs) such as nilotinib, dasatinib and ponatinib. Pleural effusion and pulmonary arterial hypertension (PAH) have been associated with dasatinib treatment. Endothelial dysfunction and impaired angiogenesis are hallmarks of PAH. In this study, we explored, at cellular and whole animal levels, the connection between dasatinib exposure and disruption of endothelial barrier integrity and function, leading to impaired angiogenesis. Understanding the mechanisms whereby dasatinib initiates PAH will provide opportunities for intervention and prevention of such adverse effects, and for future development of safer TKIs, thereby improving CML management.

Original language	English
Journal	British Journal of Haematology
DOIs	https://doi.org/10.1111/bjh.19595
Publication status	Published Online - 15 Jun 2024

Bibliographical note

We would like to thank Anna Halpern for her assistance with animal handling. We would like to thank Dr. Yael Shushlav for performing the femoral artery ligation procedures. We would like to thank Tzippy Shochat for her assistance with the statistical analyses.

This study was supported by a grant from Pfizer Pharmaceutical Company for an investigator-initiated study and by a grant from the Faculty of Medicine Research Grants, The Recanati Foundation.

Publisher Copyright:
© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

All Science Journal Classification (ASJC) codes

Hematology

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10.1111/bjh.19595Licence: CC BY-NC-ND

Cite this

Gover-Proaktor, A., Leshem-Lev, D., Winograd-Katz, S., Partouche, S., Samara, A., Shapira, S., Nardi-Agmon, I., Harari, E., Younis, A., Najjar, A., Kornowski, R., Geiger, B., Raanani, P., Leader, A., & Granot, G. (2024). Dasatinib induces endothelial dysfunction leading to impaired recovery from ischaemia. British Journal of Haematology. Advance online publication. https://doi.org/10.1111/bjh.19595

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title = "Dasatinib induces endothelial dysfunction leading to impaired recovery from ischaemia",

abstract = "Chronic myeloid leukaemia (CML) management is complicated by treatment-emergent vascular adverse events seen with tyrosine kinase inhibitors (TKIs) such as nilotinib, dasatinib and ponatinib. Pleural effusion and pulmonary arterial hypertension (PAH) have been associated with dasatinib treatment. Endothelial dysfunction and impaired angiogenesis are hallmarks of PAH. In this study, we explored, at cellular and whole animal levels, the connection between dasatinib exposure and disruption of endothelial barrier integrity and function, leading to impaired angiogenesis. Understanding the mechanisms whereby dasatinib initiates PAH will provide opportunities for intervention and prevention of such adverse effects, and for future development of safer TKIs, thereby improving CML management.",

author = "Ayala Gover-Proaktor and Dorit Leshem-Lev and Sabina Winograd-Katz and Shirly Partouche and Aladin Samara and Saar Shapira and Inbar Nardi-Agmon and Emanuel Harari and Aseel Younis and Abderrahman Najjar and Ran Kornowski and Benjamin Geiger and Pia Raanani and Avi Leader and Galit Granot",

note = "We would like to thank Anna Halpern for her assistance with animal handling. We would like to thank Dr. Yael Shushlav for performing the femoral artery ligation procedures. We would like to thank Tzippy Shochat for her assistance with the statistical analyses. This study was supported by a grant from Pfizer Pharmaceutical Company for an investigator-initiated study and by a grant from the Faculty of Medicine Research Grants, The Recanati Foundation. Publisher Copyright: {\textcopyright} 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.",

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AU - Gover-Proaktor, Ayala

AU - Leshem-Lev, Dorit

AU - Winograd-Katz, Sabina

AU - Partouche, Shirly

AU - Samara, Aladin

AU - Shapira, Saar

AU - Nardi-Agmon, Inbar

AU - Harari, Emanuel

AU - Younis, Aseel

AU - Najjar, Abderrahman

AU - Kornowski, Ran

AU - Geiger, Benjamin

AU - Raanani, Pia

AU - Leader, Avi

AU - Granot, Galit

N1 - We would like to thank Anna Halpern for her assistance with animal handling. We would like to thank Dr. Yael Shushlav for performing the femoral artery ligation procedures. We would like to thank Tzippy Shochat for her assistance with the statistical analyses. This study was supported by a grant from Pfizer Pharmaceutical Company for an investigator-initiated study and by a grant from the Faculty of Medicine Research Grants, The Recanati Foundation. Publisher Copyright: © 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

PY - 2024/6/15

Y1 - 2024/6/15

N2 - Chronic myeloid leukaemia (CML) management is complicated by treatment-emergent vascular adverse events seen with tyrosine kinase inhibitors (TKIs) such as nilotinib, dasatinib and ponatinib. Pleural effusion and pulmonary arterial hypertension (PAH) have been associated with dasatinib treatment. Endothelial dysfunction and impaired angiogenesis are hallmarks of PAH. In this study, we explored, at cellular and whole animal levels, the connection between dasatinib exposure and disruption of endothelial barrier integrity and function, leading to impaired angiogenesis. Understanding the mechanisms whereby dasatinib initiates PAH will provide opportunities for intervention and prevention of such adverse effects, and for future development of safer TKIs, thereby improving CML management.

AB - Chronic myeloid leukaemia (CML) management is complicated by treatment-emergent vascular adverse events seen with tyrosine kinase inhibitors (TKIs) such as nilotinib, dasatinib and ponatinib. Pleural effusion and pulmonary arterial hypertension (PAH) have been associated with dasatinib treatment. Endothelial dysfunction and impaired angiogenesis are hallmarks of PAH. In this study, we explored, at cellular and whole animal levels, the connection between dasatinib exposure and disruption of endothelial barrier integrity and function, leading to impaired angiogenesis. Understanding the mechanisms whereby dasatinib initiates PAH will provide opportunities for intervention and prevention of such adverse effects, and for future development of safer TKIs, thereby improving CML management.

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JO - British Journal of Haematology

JF - British Journal of Haematology

ER -

Dasatinib induces endothelial dysfunction leading to impaired recovery from ischaemia

Abstract

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