دورية أكاديمية
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: | Dumas PY; Service d'Hématologie et Thérapie Cellulaire, CHU Bordeaux, Bordeaux, France. vanessa.desplat@u-bordeaux.fr pierre-yves.dumas@u-bordeaux.fr.; BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France., Villacreces A; BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France., Guitart AV; BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France., El-Habhab A; BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France., Massara L; BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France., Mansier O; 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., Bidet A; Service d'Hématologie Biologique, CHU Bordeaux, Bordeaux, France., Martineau D; Service d'Hématologie et Thérapie Cellulaire, CHU Bordeaux, Bordeaux, France.; BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France., Fernandez S; BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France., Leguay T; Service d'Hématologie et Thérapie Cellulaire, CHU Bordeaux, Bordeaux, France., Pigneux A; Service d'Hématologie et Thérapie Cellulaire, CHU Bordeaux, Bordeaux, France.; BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France., Vigon I; BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France., Pasquet JM; BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France., Desplat V; BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France. vanessa.desplat@u-bordeaux.fr pierre-yves.dumas@u-bordeaux.fr. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Nov 01; Vol. 27 (21), pp. 6012-6025. Date of Electronic Publication: 2021 Aug 16. |
| نوع المنشور: | Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Aniline Compounds/*pharmacology , Aniline Compounds/*therapeutic use , Benzothiazoles/*pharmacology , Benzothiazoles/*therapeutic use , Drug Resistance, Neoplasm/*drug effects , Leukemia, Myeloid, Acute/*drug therapy , Phenylurea Compounds/*pharmacology , Phenylurea Compounds/*therapeutic use , Proto-Oncogene Proteins/*antagonists & inhibitors , Pyrazines/*pharmacology , Pyrazines/*therapeutic use , Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors , fms-Like Tyrosine Kinase 3/*antagonists & inhibitors , fms-Like Tyrosine Kinase 3/*physiology, Cell Line, Tumor ; Hematopoiesis ; Humans ; Axl Receptor Tyrosine Kinase |
| مستخلص: | 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. (©2021 American Association for Cancer Research.) |
| References: | Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100:1532–42. Choudhary C, Brandts C, Schwable J, Tickenbrock L, Sargin B, Ueker A, et al. Activation mechanisms of STAT5 by oncogenic Flt3-ITD. Blood. 2007;110:370–4. Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909–18. Smith CC, Wang Q, Chin C-S, Salerno S, Damon LE, Levis MJ, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012;485:260–3. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454–64. Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16:1691–9. Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20:984–97. Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381:1728–40. Sexauer A, Perl A, Yang X, Borowitz M, Gocke C, Rajkhowa T, et al. Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML. Blood. 2012;120:4205–14. McMahon CM, Canaani J, Rea B, Sargent RL, Qualtieri JN, Watt CD, et al. Gilteritinib induces differentiation in relapsed and refractory FLT3-mutated acute myeloid leukemia. Blood Adv. 2019;3:1581–5. Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 2014;14:769–85. Ben-Batalla I, Schultze A, Wroblewski M, Erdmann R, Heuser M, Waizenegger JS, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood. 2013;122:2443–52. Park I-K, Mundy-Bosse B, Whitman SP, Zhang X, Warner SL, Bearss DJ, et al. Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia. Leukemia. 2015;29:2382–9. Dumas P-Y, Naudin C, Martin-Lannerée S, Izac B, Casetti L, Mansier O, et al. Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5- and hypoxia- dependent up-regulation of AXL. Haematologica. 2019;104:2017–27. Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–8. Guitart AV, Panagopoulou TI, Villacreces A, Vukovic M, Sepulveda C, Allen L, et al. Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions. J Exp Med. 2017;214:719–35. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7:27–31. Retmana IA, Wang J, Schinkel AH, Schellens JHM, Beijnen JH. Sparidans RW. Liquid chromatography-tandem mass spectrometric assay for the quantitative determination of the tyrosine kinase inhibitor quizartinib in mouse plasma using salting-out liquid-liquid extraction. J Chromatogr B Analyt Technol Biomed Life Sci. 2017;1061–1062:300–5. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009;114:2984–92. Sandmaier BM, Khaled S, Oran B, Gammon G, Trone D, Frankfurt O. Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant. Am J Hematol. 2018;93:222–31. Mori M, Kaneko N, Ueno Y, Yamada M, Tanaka R, Saito R, et al. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017;35:556–65. James AJ, Smith CC, Litzow M, Perl AE, Altman JK, Shepard D, et al. Pharmacokinetic profile of gilteritinib: A novel FLT-3 tyrosine kinase inhibitor. Clin Pharmacokinet. 2020;59:1273–90. Verma A, Warner SL, Vankayalapati H, Bearss DJ, Sharma S. Targeting Axl and Mer kinases in cancer. Mol Cancer Ther. 2011;10:1763–73. Gioia R, Trégoat C, Dumas P-Y, Lagarde V, Prouzet-Mauléon V, Desplat V, et al. CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukaemia. J Pathol. 2015;237:14–24. Rochlitz C, Lohri A, Bacchi M, Schmidt M, Nagel S, Fopp M, et al. Axl expression is associated with adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia (AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK). Leukemia. 1999;13:1352–8. Whitman SP, Kohlschmidt J, Maharry K, Volinia S, Mrózek K, Nicolet D, et al. GAS6 expression identifies high-risk adult AML patients: potential implications for therapy. Leukemia. 2014;28:1252–8. Hong C-C, Lay J-D, Huang J-S, Cheng A-L, Tang J-L, Lin M-T, et al. Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 2008;268:314–24. Park I-K, Mishra A, Chandler J, Whitman SP, Marcucci G, Caligiuri MA. Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target. Blood. 2013;121:2064–73. Korn C, Méndez-Ferrer S. Myeloid malignancies and the microenvironment. Blood. 2017;129:811–22. Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol. 2017;18:1061–75. Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018;9:889–903. Taylor SJ, Duyvestyn JM, Dagger SA, Dishington EJ, Rinaldi CA, Dovey OM, et al. Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib. Sci Transl Med. 2017;9. |
| المشرفين على المادة: | 0 (Aniline Compounds) 0 (Benzothiazoles) 0 (Phenylurea Compounds) 0 (Proto-Oncogene Proteins) 0 (Pyrazines) 0 (gilteritinib) 7LA4O6Q0D3 (quizartinib) EC 2.7.10.1 (FLT3 protein, human) EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) EC 2.7.10.1 (fms-Like Tyrosine Kinase 3) 0 (Axl Receptor Tyrosine Kinase) 0 (AXL protein, human) |
| تواريخ الأحداث: | Date Created: 20210817 Date Completed: 20220331 Latest Revision: 20221213 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1158/1078-0432.CCR-20-3114 |
| PMID: | 34400415 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3265 |
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| DOI: | 10.1158/1078-0432.CCR-20-3114 |