Abstract
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.
Highlights
Mutations in the FMS-like tyrosine kinase 3 gene (FLT3), involved in regulating survival, proliferation, and differentiation of hematopoietic stem/progenitor cells [1], are common in acute myeloid leukemia (AML)
We investigated the efficacy and molecular mechanisms for the strategy to overcome the extrinsic resistance to FLT3 inhibitors in FLT3-internal tandem duplications (ITD)-AML by disrupting the
CXCL12/CXCR4 axis is a promising strategy to overcome extrinsic resistance observations indicate that targeting the CXCL12/CXCR4 axis is a promising strategy to overcome by the protective
Summary
Mutations in the FMS-like tyrosine kinase 3 gene (FLT3), involved in regulating survival, proliferation, and differentiation of hematopoietic stem/progenitor cells [1], are common in acute myeloid leukemia (AML). These alterations confer inferior response to chemotherapy and poor overall survival, when they occur as internal tandem duplications (ITD) in the juxtamembrane domain whereas activating point mutations in the second tyrosine kinase domain have no significant impact on outcomes [2]. FLT3-ITD mutations constitutively activate phosphatidyl-inositol 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and signal transducer and activator of transcription 5 (STAT5) pathways and result in uncontrolled cell proliferation and cell survival [3,4]. Three FLT3 inhibitors, including midostaurin, gilteritinib, and quizartinib have been approved for the treatment of FLT3-ITD positive
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