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Open AccessArticle

CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-β Signaling

1
Leukemia Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
2
Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
3
Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
4
Department of Pathology, College of Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
5
Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
6
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
7
Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(7), 1737; https://doi.org/10.3390/cancers12071737
Received: 3 April 2020 / Revised: 18 April 2020 / Accepted: 20 April 2020 / Published: 30 June 2020
(This article belongs to the Special Issue Targeting the Tumor Microenvironment)
Given the proven importance of the CXCL12/CXCR4 axis in the stroma–acute myeloid leukemia (AML) interactions and the rapid emergence of resistance to FLT3 inhibitors, we investigated the efficacy and safety of a novel CXCR4 inhibitor, LY2510924, in combination with FLT3 inhibitors in preclinical models of AML with FLT3-ITD mutations (FLT3-ITD-AML). Quizartinib, a potent FLT3 inhibitor, induced apoptosis in FLT3-ITD-AML, while LY2510924 blocked surface CXCR4 without inducing apoptosis. LY2510924 significantly reversed stroma-mediated resistance against quizartinib mainly through the MAPK pathway. In mice with established FLT3-ITD-AML, LY2510924 induced durable mobilization and differentiation of leukemia cells, resulting in enhanced anti-leukemia effects when combined with quizartinib, whereas transient effects were seen on non-leukemic blood cells in immune-competent mice. Sequencing of the transcriptome of the leukemic cells surviving in vivo treatment with quizartinib and LY2510924 revealed that genes related to TGF-β signaling may confer resistance against the drug combination. In co-culture experiments of FLT3-ITD-AML and stromal cells, both silencing of TGF-β in stromal cells or TGF-β-receptor kinase inhibitor enhanced apoptosis by combined treatment. Disruption of the CXCL12/CXCR4 axis in FLT3-ITD-AML by LY2510924 and its negligible effects on normal immunocytes could safely enhance the potency of quizartinib, which may be further improved by blockade of TGF-β signaling. View Full-Text
Keywords: CXCR4; FLT3-ITD; acute myeloid leukemia; LY2510924; quizartinib CXCR4; FLT3-ITD; acute myeloid leukemia; LY2510924; quizartinib
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Kim, B.-R.; Jung, S.-H.; Han, A.-R.; Park, G.; Kim, H.-J.; Yuan, B.; Battula, V.L.; Andreeff, M.; Konopleva, M.; Chung, Y.-J.; Cho, B.-S. CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-β Signaling. Cancers 2020, 12, 1737.

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