Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML

Abstract

IntroductionNormal and leukemic hematopoietic cells and stem cells reside in the bone marrow in specialized areas ("niches") that provide the structural and physiologic conditions for their growth and survival. 1 Subpopulations of leukemic cells can be sequestered in niches and thereby evade chemotherapy-induced death. 2 We and others have reported that stromal cells protect acute myeloid leukemia (AML) and chronic lymphocytic leukemia cells from the apoptosis induced by chemotherapy. [3][4][5][6] While the mechanisms of stroma-mediated protection are pleiotropic and involve a complex interplay of stroma-produced cytokines, chemokines, and adhesion molecules, the stroma-secreted chemokine stromal-derived factor 1␣ (SDF-1␣) and its cognate receptor CXCR4 have recently emerged as critical mediators of stromal/leukemic cell interactions. 7,8 SDF-1␣ and CXCR4 primarily regulate the migration, homing, and mobilization of hematopoietic cells. 9,10 Binding of SDF-1␣ to CXCR4 causes CXCR4 to be incorporated into lipid rafts 11 and increases its phosphorylation. 12 The latter leads to prolonged activation of the extracellular signaling-regulated kinase (ERK) and phosphoinositol 3-kinase (PI3K) pathways, 13 which are key signaling pathways that promote leukemia cells survival. 14,15 Both surface and intracellular 16 CXCR4 levels were found to be elevated in a subset of AML cases. Further, CXCR4 has been shown to mediate the homing and engraftment of AML cells to the bone marrow of nonobese diabetes (NOD)/severe combined immunodeficiency (SCID) mice. 17,18 Finally, CXCR4 was recently reported to be expressed at higher levels in cases of AML associated with an internal tandem duplication (ITD) type of mutation of the gene that encodes fetal liver tyrosine . 19 This is one of the most frequent mutations in AML, which confers poor response to chemotherapy and only transient response to FLT3 inhibitors. 20,21 Our recent studies, in addition, indicated that CXCR4 expression is associated with poor prognosis in patients with diploid AML regardless of FLT3 mutation status. 22,23 Altogether, these findings suggest that disruption of these interactions by SDF-1␣/CXCR4 antagonists represents a novel strategy for targeting leukemia/bone marrow microenvironment interactions. We have reported that inhibition of CXCR4 by specific synthetic peptides (ie, RCP168) interferes with stromal/ leukemic cell interactions and increases the sensitivity of leukemic cells to chemotherapy. 24 In this study, we used AMD3465 (Anormed and Genzyme, Cambridge, MA), a second-generation smallmolecule reversible inhibitor of SDF-1␣/CXCR4 with a half maximal inhibitory concentration (IC 50 An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use on...

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

“…24,26 CXCR4 inhibitors induced mobilization of AML cells into circulation and enhanced antileukemic effects of chemotherapy, resulting in markedly reduced leukemia burden and prolonged survival. 25 These effects resemble those of AML cell stimulation by G-CSF or GM-CSF, and synergy between the activities of hematopoietic growth factors (at least G-CSF) and CXCR4 inhibitors has been reported. [27][28][29] A mechanism of action for the beneficial effect of priming with GM-CSF could, therefore, be mediated through CXCR4-induced mobilization.…”

“…22,23 Inhibition of CXCR4 has been able to overcome resistance to numerous drugs. 24,25 CXCR4 inhibitors that target the stromal interaction and release the leukemic cells from the microenvironment have both a mobilizing and cell-cycle activating effect upon leukemic cells and may sensitize AML for chemotherapeutic cell killing. 24,26 CXCR4 inhibitors induced mobilization of AML cells into circulation and enhanced antileukemic effects of chemotherapy, resulting in markedly reduced leukemia burden and prolonged survival.…”

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

“…102 CXCR4 inhibition results in disruption of AML-niche interactions and sensitizes leukemic blasts to cytotoxic chemotherapy. [103][104][105] Thus, CXCR4/FLT3 combination therapy might preferentially target FLT3-ITD cells. This combination is currently being evaluated in a phase 1 clinical trial.…”

“…These agents may make AML stem cells more accessible for eradication by FLT3 inhibitors and chemotherapeutic agents. Proof of concept for this approach has been established in a mouse model of AML, 105 and combination therapies with FLT3 inhibitors and stem cell mobilizers are currently being evaluated in clinical trials.…”

Drug resistance in mutant FLT3-positive AML

“…Mutant FLT3 activates CXCR4 signaling, and CXCR4 inhibition partially overcomes stromal-mediated cytoprotection of FLT3 inhibitor-treated AML cells (Zeng et al, 2009). In vivo, the CXCR4 inhibitor, AMD3465, lowered leukemia burden and enhanced survival through mobilization of AML cells and progenitor cells into circulation, and potentiation of the antileukemic effects of the FLT3 inhibitor, sorafenib, and chemotherapy (Zeng et al, 2009).…”