Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis
| Autor: | Joseph E. Italiano, Prakrith Vijey, Thomas S. Soussou, Yosef Landesman, Boris Klebanov, Zhi-Jian Liu, Stephen Wu, Martha Sola-Visner, Thaddeus J. Unger, Trinayan Kashyap, Eran Shacham, Marsha Crochiere, Kellie R. Machlus |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Blood Platelets medicine.medical_treatment Immunology Apoptosis Cell Count Pharmacology Biochemistry Thrombopoiesis 03 medical and health sciences 0302 clinical medicine Fetus In vivo Bone Marrow hemic and lymphatic diseases medicine Animals Adverse effect Thrombopoietin Megakaryopoiesis Mice Knockout Chemotherapy Dose-Response Relationship Drug business.industry Stem Cells Cell Differentiation Cell Biology Hematology Drug holiday Triazoles Platelets and Thrombopoiesis Platelet Activation Thrombocytopenia Clinical trial 030104 developmental biology Hydrazines Liver 030220 oncology & carcinogenesis Cancer research Stem cell business Megakaryocytes Signal Transduction |
| Zdroj: | Blood. 130(9) |
| ISSN: | 1528-0020 |
| Popis: | Selinexor is the first oral selective inhibitor of nuclear export compound tested for cancer treatment. Selinexor has demonstrated a safety therapy profile with broad antitumor activity against solid and hematological malignancies in phases 2 and 3 clinical trials (#NCT03071276, #NCT02343042, #NCT02227251, #NCT03110562, and #NCT02606461). Although selinexor shows promising efficacy, its primary adverse effect is high-grade thrombocytopenia. Therefore, we aimed to identify the mechanism of selinexor-induced thrombocytopenia to relieve it and improve its clinical management. We determined that selinexor causes thrombocytopenia by blocking thrombopoietin (TPO) signaling and therefore differentiation of stem cells into megakaryocytes. We then used both in vitro and in vivo models and patient samples to show that selinexor-induced thrombocytopenia is indeed reversible when TPO agonists are administered in the absence of selinexor (drug holiday). In sum, these data reveal (1) the mechanism of selinexor-induced thrombocytopenia, (2) an effective way to reverse the dose-limiting thrombocytopenia, and (3) a novel role for XPO1 in megakaryopoiesis. The improved selinexor dosing regimen described herein is crucial to help reduce thrombocytopenia in selinexor patients, allowing them to continue their course of chemotherapy and have the best chance of survival. This trial was registered at www.clinicaltrials.gov as #NCT01607905. |
| Databáze: | OpenAIRE |
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