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Mitoxantrone-liposome sensitizes Flt3-ITD acute myeloid leukemia to gilteritinib treatment

ABSTRACT: FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia (AML), and is associated with a poor prognosis and high relapse rate. Gilteritinib, as a second-generation FLT3 inhibitor, is an important target drug in the treatment of FLT3-ITD AML patients, but it still faces the problems of drug resistance and reduced potency. In this study, we found that mitoxantrone-liposome can sensensitized gilteritinib and enhanced the therapeutic effect in vivo and in vitro. RNA-sequencing revealed that the combination treatment resulted in specific changes in gene expression, reduced drug resistance and the mechanism. Primary AML cells harvested from patients with FLT3-ITD AML showed a significant response to combination treatment in vitro. Our data suggest represents a novel and promising therapeutic strategy for FLT3-ITD AML patients and relapsed/refractory(R/R) AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276384 | GEO | 2025/03/19

REPOSITORIES: GEO

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Mitoxantrone-liposome sensitizes Flt3-ITD acute myeloid leukemia to gilteritinib treatment

Project description:Mitoxantrone-liposome sensitizes Flt3-ITD acute myeloid leukemia to gilteritinib treatment

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2022-08-25 | PXD023123 | Pride

BMX Kinase Mediates Gilteritinib Resistance in FLT3-mutated AML through Microenvironmental Factors

Project description:While clinical benefit has been observed with gilteritinib, most patients relapse through unknown mechanisms. To investigate mechanisms of gilteritinib resistance, we performed targeted genomic sequencing and single cell (sc) RNASeq on primary FLT3-ITD-mutated AML samples. Co-occurring mutations in RAS pathway genes were the most common. In gilteritinib-unresponsive patients, increased expression of bone marrow-derived hematopoietic cytokines and chemokines was observed after treatment compared to gilteritinib-sensitive patients. Expression of the TEK-family kinase, BMX, was higher in gilteritinib-unresponsive patients after treatment compared to gilteritinib-sensitive patients. BMX contributed to gilteritinib resistance in FLT3-mutant cells lines in a hypoxia-dependent manner by promoting pSTAT5 signaling, which was reversed with pharmacological inhibition and genetic knockout. In primary FLT3-mutated AML samples, pharmacological inhibition of BMX enhanced the antileukemic activity of gilteritinib and decreased chemokine expression. Gene module analysis associated gilteritinib responsiveness with lymphocyte differentiation and myeloid leukocyte activation. By contrast, unresponsiveness to gilteritinib associated with upregulation of cell-cycle, DNA/RNA metabolic processes, and protein translation. Together, these data support a role for microenvironment-mediated factors modulated by BMX in the escape from targeted therapy and gilteritinib resistance. This analysis provides a deeper understanding of targets and pathways for potential therapeutic intervention to restore gilteritinib sensitivity.

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Translatome proteomics of human AML cells treated with FLT3 inhibitors quizartinib, crenolanib, gilteritinib

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shCDK9 or shDHODH sensitizes cells to gilteritinib treatment by altering transcriptomes of AML cells

Project description:Acquisition of an internal tandem duplication of the juxtamembrane region of FLT3 (FLT3-ITD) is a common event in Acute myeloid leukemia (AML) patients and is associated with poor outcomes at high allelic frequency. Although targeted therapies against FLT3-ITD exist, narrow therapeutic index as monotherapies and failure to achieve complete remission limits their clinical application. Using a genome-wide CRISPR knockout screen, we identified cyclin-dependent kinase (CDK9), protein arginine methyltransferase (PRMT5) and dihydroorotate dehydrogenase (DHODH) as novel synthetic lethal partners with gilteritinib treatment. We demonstrated that genetic or pharmacologic inhibition of these targets in combination with gilteritinib synergistically kill AML cells. The presence of FLT3-ITD was shown to cause a significant increase in aerobic glycolysis, rending the leukemia cells highly sensitive to pharmacological inhibition of glycolytic activity. Supportive of this, our screen shows that sgRNAs targeting ~28 genes in the glycolysis pathway are enriched in cells treated with gilteritinib, suggesting that switching to oxidative phosphorylation from aerobic glycolysis may represent a metabolic adaption of the leukemic cells to resistance to FLT3-targeted therapy. Interestingly, the knockdown of CDK9, PRMT5 or DHODH in presence of gilteritinib cooperatively shuts down oxidative phosphorylation and associated purine biosynthesis and mevalonate pathway, implying inhibition of these genes along with proteins involved in the mitochondria respiratory chain complexes and energy metabolism may represent an attractive strategy to resensitize leukemic cells to gilteritinib treatment. Overall, these findings provide the basis for maximizing therapeutic impact of FLT3-ITD inhibitors and provide a rationale for a clinical trial of these novel combinatorial therapies.

2022-09-21 | GSE185519 | GEO

Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in Acute Myeloid Leukemia

Project description:Purpose: Compare transcriptional changes between drug treated (gilteritinib, TP-0903) and vehicle in acute myeloid leukemia xenografts. Methods: FLT3-ITD+ MOLM13-RES-Luc+ (MOLM13 cells with a D835Y mutation generating a resistant phenotype) AML cells were xenografted into NSG mice. Mice were randomized according to bioluminescence imaging, and treatment of FLT3 tyrosine kinase inhibitor (gilteritinib, 30 mg/kg, once daily for 5 days/week) was started on day 13 post-tail vein injection. At study end point, mice were humanely euthanized and bone marrow was collected. AML cells (human CD45+) were isolated, and ATAC-seq was performed on HiSeq 4000, total RNA. Sequencing reads were aligned and analyzed for differential gene expression of treatment vs vehicle cohorts. Results: The analysis revealed the chromatin accessibility changes induced by gilteritinib in MOLM13-RES AML xenograft model.

2021-07-07 | GSE179421 | GEO

Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in Acute Myeloid Leukemia (RNA-Seq II)

Project description:Purpose: Compare transcriptional changes between drug treated (gilteritinib, TP-0903) and vehicle in acute myeloid leukemia xenografts. Methods: FLT3-ITD+ MOLM13-Luc+ AML cells were xenografted into NSG mice. Mice were randomized according to bioluminescence imaging, and treatment of FLT3 tyrosine kinase inhibitors (TP-0903, 60 mg/kg, once daily for 5 days/week; gilteritinib, 30 mg/kg, once daily for 5 days/week) was started on day 7 post-tail vein injection. At study end point, mice were humanely euthanized and bone marrow was collected. AML cells (human CD45+) were isolated, and RNA-seq was performed on total RNA. Sequencing reads were aligned and analyzed for differential gene expression of treatment vs vehicle cohorts. Results: The analysis revealed the transcriptional changes induced by TP-0903 or gilteritinib in MOLM13 AML xenograft model.

2021-07-22 | GSE180181 | GEO

Alkynyl nicotinamides with antileukemic activity to treat poor prognosis AM

Project description:FLT3 activating mutations cause myeloproliferative neoplasms by deregulating hematopoietic progenitor cell growth, and acute myeloid leukemia is on the rise. Investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop inherent and acquired resistance to FLT3 targeted therapy. FLT3 inhibitor resistance in AML is dependent on co-occurring mutations, parallel survival pathways, and/or subsequent FLT3-ITD mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options. We identified two novel naphthyridine-based FLT3 inhibitors (HSN608 and HSN748) that specifically target FLT3-ITD at sub-nanomolar concentrations and are effective against drug-resistant secondary mutations. In the current study, we evaluated these compounds antileukemic activity against FLT3-ITD and gatekeeper mutations in drug-resistant AML, relapsed/refractory AMLs with FLT3 mutations, and in vivo mouse models with combinations of epigenetic mutations TET2 with FLT3-ITD, and AML patients PDX. In these model systems, we demonstrate that HSN748 outperforms the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3-ITD.

2022-12-07 | MSV000090855 | MassIVE

Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in Acute Myeloid Leukemia (RNA-Seq I)

Project description:Purpose: Compare transcriptional changes between drug treated (gilteritinib, TP-0903) and vehicle in acute myeloid leukemia xenografts. Methods: FLT3-ITD+ MOLM13-RES-Luc+ (MOLM13 cells with a D835Y mutation generating a resistant phenotype) AML cells were xenografted into NSG mice. Mice were randomized according to bioluminescence imaging, and treatment of FLT3 tyrosine kinase inhibitors (TP-0903, 60 mg/kg, once daily for 5 days/week; gilteritinib, 30 mg/kg, once daily for 5 days/week) was started on day 13 post-tail vein injection. At study end point, mice were humanely euthanized and bone marrow was collected. AML cells (human CD45+) were isolated, and RNA-seq was performed on total RNA. Sequencing reads were aligned and analyzed for differential gene expression of treatment vs vehicle cohorts. Results: The analysis revealed the transcriptional changes induced by TP-0903 or gilteritinib in MOLM13-RES AML xenograft model.

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