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Dual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in -ITD Acute Myeloid Leukemia.

dc.rights.licenseauthentificationen_US
dc.contributor.authorDUMAS, Pierre-Yves
dc.contributor.authorVILLACRECES, Arnaud
dc.contributor.authorGUITART, Amélie V
dc.contributor.authorEL-HABHAB, Ali
dc.contributor.authorMASSARA, Layal
hal.structure.identifierBiologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases
dc.contributor.authorMANSIER, Olivier
dc.contributor.authorBIDET, Audrey
dc.contributor.authorMARTINEAU, Delphine
dc.contributor.authorFERNANDEZ, Solene
dc.contributor.authorLEGUAY, Thibaut
dc.contributor.authorPIGNEUX, Arnaud
dc.contributor.authorVIGON, Isabelle
dc.contributor.authorPASQUET, Jean-Max
dc.contributor.authorDESPLAT, Vanessa
dc.date.accessioned2021-10-21T10:14:33Z
dc.date.available2021-10-21T10:14:33Z
dc.date.issued2021-08-16
dc.identifier.issn1557-3265en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/112867
dc.description.abstractEnAXL has been shown to play a pivotal role in the selective response of -ITD acute myeloid leukemia (AML) cells to FLT3 tyrosine kinase inhibitors (TKI), particularly within the bone marrow microenvironment. Herein, we compared the effect of dual FLT3/AXL-TKI gilteritinib with quizartinib through models mimicking hematopoietic niche conditions, in primary AML blasts, and with dosing regimens allowing plasma concentration close to those used in clinical trials. 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. , 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, -ITD AML patient-derived xenografts revealed that this effect was particularly reproducible in -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. 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 -ITD signaling.
dc.description.abstractEnLeukemia, AML, FTL3-ITD, TKI, AXL, Gilteritinib, ASP2215, Microenvironment
dc.language.isoENen_US
dc.title.enDual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in -ITD Acute Myeloid Leukemia.
dc.title.alternativeClin Cancer Resen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1158/1078-0432.CCR-20-3114en_US
dc.subject.halSciences du Vivant [q-bio]/Médecine humaine et pathologieen_US
dc.identifier.pubmed34400415en_US
bordeaux.journalClinical Cancer Researchen_US
bordeaux.hal.laboratoriesBiologie des maladies cardiovasculaires (BMC) - UMR 1034en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.exportfalse
workflow.import.sourcepubmed
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Clinical%20Cancer%20Research&rft.date=2021-08-16&rft.eissn=1557-3265&rft.issn=1557-3265&rft.au=DUMAS,%20Pierre-Yves&VILLACRECES,%20Arnaud&GUITART,%20Am%C3%A9lie%20V&EL-HABHAB,%20Ali&MASSARA,%20Layal&rft.genre=article


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