Dual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in FLT3 -ITD Acute Myeloid Leukemia
| العنوان: | Dual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in FLT3 -ITD Acute Myeloid Leukemia |
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| المؤلفون: | Arnaud Villacreces, Olivier Mansier, Isabelle Vigon, Jean-Max Pasquet, Audrey Bidet, Pierre-Yves Dumas, Amelie V. Guitart, Arnaud Pigneux, Vanessa Desplat, Ali El-habhab, Solène Fernandez, Layal Massara, Delphine Martineau, Thibaut Leguay |
| المساهمون: | CHU Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire, F-33000 Bordeaux, France., BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France, INSERM U1034, Institut National de la Santé et de la Recherche Médicale, University of Bordeaux, Bordeaux, France, Service d'Hématologie Biologique, CHU Bordeaux, Bordeaux, France, Centre National de la Recherche Scientifique (CNRS), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Biologique [CHU Bordeaux], CHU Bordeaux [Bordeaux], Vigon, Isabelle |
| المصدر: | Clinical Cancer Research Clinical Cancer Research, American Association for Cancer Research, 2021, 27 (21), pp.6012-6025. ⟨10.1158/1078-0432.CCR-20-3114⟩ Clinical Cancer Research, 2021, 27 (21), pp.6012-6025. ⟨10.1158/1078-0432.CCR-20-3114⟩ Clinical Cancer Research, American Association for Cancer Research, 2021, ⟨10.1158/1078-0432.CCR-20-3114⟩ |
| بيانات النشر: | HAL CCSD, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, Stromal cell, FLT3-ITD, [SDV]Life Sciences [q-bio], 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, AML, In vivo, hemic and lymphatic diseases, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Quizartinib, 0303 health sciences, Chemistry, leukemia, Myeloid leukemia, AXL, Gilteritinib, TKI, microenvironment, 3. Good health, [SDV] Life Sciences [q-bio], Haematopoiesis, ASP2215, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, Bone marrow, Tyrosine kinase, Ex vivo |
| الوصف: | Purpose: AXL has been shown to play a pivotal role in the selective response of FLT3-ITD acute myeloid leukemia (AML) cells to FLT3 tyrosine kinase inhibitors (TKI), particularly within the bone marrow microenvironment. Experimental Design: Herein, we compared the effect of dual FLT3/AXL-TKI gilteritinib with quizartinib through in vitro models mimicking hematopoietic niche conditions, ex vivo in primary AML blasts, and in vivo with dosing regimens allowing plasma concentration close to those used in clinical trials. Results: We observed that gilteritinib maintained a stronger proapoptotic effect in hypoxia and coculture with bone marrow stromal cells compared with quizartinib, linked to a dose-dependent inhibition of AXL phosphorylation. In vivo, use of the MV4–11 cell line with hematopoietic engraftment demonstrated that gilteritinib was more effective than quizartinib at targeting leukemic cells in bone marrow. Finally, FLT3-ITD AML patient-derived xenografts revealed that this effect was particularly reproducible in FLT3-ITD AML with high allelic ratio in primary and secondary xenograft. Moreover, gilteritinib and quizartinib displayed close toxicity profile on normal murine hematopoiesis, particularly at steady state. Conclusions: Overall, these findings suggest that gilteritinib as a single agent, compared with quizartinib, is more likely to reach leukemic cells in their protective microenvironment, particularly AML clones highly dependent on FLT3-ITD signaling. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1078-0432 1557-3265 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::21c67dd36a63f2ce88ba9a920629e5ab https://hal.archives-ouvertes.fr/hal-03455205 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....21c67dd36a63f2ce88ba9a920629e5ab |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10780432 15573265 |
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