Glucocorticoids enhance the anti-leukemic activity of FLT3 inhibitors in FLT3 mutant acute myeloid leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA478462 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Utilizing genome wide transcriptome analysis and drug screen we demonstrate that upregulation of inflammatory pathways is a key mechanism of drug tolerance to FLT3 targeted inhibitors in AML
2020-09-02 | GSE116432 | GEO
Project description:Internal tandem duplications in the tyrosine kinase receptor FLT3 (FLT3-ITD) are among the most common lesions in acute myeloid leukemia (AML) and there exists a need for new forms of treatment. Using ex vivo drug sensitivity screening, we found that FLT3-ITD+ patient cells are particularly sensitive to HSP90 inhibitors. While it is well known that HSP90 is important for FLT3-ITD stability, we found that HSP90 family members play a much more complex role in FLT3-ITD signaling than previously appreciated. First, we found that FLT3-ITD activates the unfolded protein response (UPR), leading to increased expression of GRP94/HSP90B1. GRP94 rewires FLT3-ITD signaling by binding and retaining FLT3-ITD in the ER, where it aberrantly activates downstream signaling pathways. Second, HSP90 family proteins protect FLT3-ITD+ AML cells against apoptosis by alleviating proteotoxic stress, and treatment with HSP90 inhibitors results in proteotoxic overload that triggers UPR-induced apoptosis. Importantly, leukemic stem cells are strongly dependent upon HSP90 for their survival, and the HSP90 inhibitor ganetespib causes leukemic stem cell exhaustion in mouse PDX models. Taken together, our study reveals a molecular basis for HSP90 addiction of FLT3-ITD+ AML cells and provides a rationale for including HSP90 inhibitors in the treatment regime for FLT3-ITD+ AML.
2020-09-02 | PXD009423 | Pride
Project description:FLT3 is a frequently mutated gene that is highly associated with a poor prognosis in acute myeloid leukemia (AML). Despite initially responding to FLT3 inhibitors, most patients eventually relapse with drug resistance. The mechanism by which resistance arises and the initial response to drug treatment that promotes cell survival is unknown. Recent studies show that a transiently maintained subpopulation of drug-sensitive cells, so-called drug-tolerant "persisters" (DTPs), can survive cytotoxic drug exposure despite lacking resistance-conferring mutations. Using RNA sequencing and drug screening, we find that treatment of FLT3 internal tandem duplication AML cells with quizartinib, a selective FLT3 inhibitor, upregulates inflammatory genes in DTPs and thereby confers susceptibility to anti-inflammatory glucocorticoids (GCs). Mechanistically, the combination of FLT3 inhibitors and GCs enhances cell death of FLT3 mutant, but not wild-type, cells through GC-receptor-dependent upregulation of the proapoptotic protein BIM and proteasomal degradation of the antiapoptotic protein MCL-1. Moreover, the enhanced antileukemic activity by quizartinib and dexamethasone combination has been validated using primary AML patient samples and xenograft mouse models. Collectively, our study indicates that the combination of FLT3 inhibitors and GCs has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in FLT3-mutant AML.
| S-EPMC7453151 | biostudies-literature
Project description:Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in 25% of acute myeloid leukemia (AML) patients and lead to constitutive activation of FLT3, driving leukemia cell survival and proliferation. Quizartinib, crenolanib and gilteritinib are second-generation FLT3 inhibitors (FLT3i) in phase III trials or clinical use for the targeted treatment of FLT3-ITD+ AML. However, they demonstrated only limited benefit and were not curative. A full understanding of cellular resistance factors contributing to this poor response is lacking. Here, we examined cell-autonomous pathways modulated by FLT3i using global translatome and phosphoproteome proteomics to identify non-genetic resistance mechanisms.
2022-08-25 | PXD023125 | Pride
Project description:Primary human AML cells (newly diagnosed, prior to treatment initation) was obtained from donor after consent and AML blasts were isolated by standard Ficoll centrifugation. Cells were treated ex vivo with DMSO vehicle control or 10 nM FLT3 inhibitors quizartinib, crenolanib, gilteritinib for 6 hours in SILAC medium and processed for LC/MS.
2022-08-25 | PXD034081 | Pride
Project description:Acute myeloid leukemia (AML) is a clonal hematopoietic malignancy, characterized by expansion of immature leukemic blasts in the bone marrow. In AML, specific tyrosine kinases have been implicated in leukemogenesis, and are associated with poor treatment outcome. However, targeted therapy using kinase inhibitors (KIs) has had limited success, and may be improved by proper patient selection. We performed phosphotyrosine (pY) based, label-free phosphoproteomics to identify hyperphosphorylated, active kinases in two FLT3+ AML Pt samples.
2020-03-02 | PXD015639 | Pride
Project description:The interaction of Menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and potential therapeutic opportunity against NPM1 mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. Transcriptional profiling upon pharmacological inhibition of the Menin-MLL complex revealed specific changes in gene expression with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being most pronounced. Combining Menin-MLL inhibition with specific small molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream to FLT3 signaling. The drug combination induced synergistic inhibition of proliferation as well as enhanced apoptosis and differentiation compared to single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary AML cells harvested from patients with NPM1mut FLT3mut AML showed significantly better responses to combined Menin and FLT3 inhibition than to single-drug or vehicle control treatment, while AML cells with wildtype NPM1, MLL, and FLT3 were not affected by any of the two drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared to the single-drug and vehicle control groups. Our data suggest that combined Menin-MLL and FLT3 inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.
2020-07-01 | GSE144759 | GEO
Project description:Adaptive resistance is an important mechanism of resistance to tyrokine kinase inhibitors in cancer. With this study we aimed to determine which signaling pathways may contribute to adaptive resistance by examining the mRNA profiles of FLT3-ITD AML cells treated with the FLT3 inhibitor, AC220. We also aimed to determine whether our novel inhibitor, NCGC1481, would inhibit the activation of these pathways. We concluded that AC220 induces activation of innate immune signaling and NCGC1481 prevents this activation.
2020-02-03 | GSE121272 | GEO
Project description:we observed synergistic cytotoxic effects, preferentially reducing cell proliferation and inducing apoptosis in FLT3/ITD+ AML cell lines and in primary AML cells. Furthermore, the combination of FLT3-TKI and GSI eradicated leukemic cells and prolonged survival in a FLT3/ITD+ patient derived xenograft (PDX) AML model. Mechanistically, decreased expression of CXCR3 that lead to down-regulated ERK signaling was partially responsible for the observed synergy. Our findings suggest that combined therapies of FLT3-TKIs with GSI may be exploited as a potential therapeutic strategy to treat FLT3/ITD+ AML.
2019-02-23 | GSE126933 | GEO
Project description:With the aim of finding small molecules that stimulate erythropoiesis earlier than erythropoietin and that enhance CFU-E production, we studied the mechanism by which glucocorticoids increase CFU-E formation. Using BFU-E and CFU-E progenitors purified by a new technique, we demonstrate that glucocorticoids stimulate the earliest (BFU-E) progenitors to undergo limited self-renewal, which increases formation of CFU-E cells > 20-fold. Interestingly, glucocorticoids induce expression of genes in BFU-E cells that contain promoter regions highly enriched for hypoxia-induced factor 1 alpha (HIF1a) binding sites. This suggests activation of HIF1a may enhance or replace the effect of glucocorticoids on BFU-E self-renewal. Indeed, HIF1a activation by a prolyl hydroxylase inhibitor (PHI) synergizes with glucocorticoids and enhances production of CFU-Es 170-fold. Since PHIs are able to increase erythroblast production at very low concentrations of glucocorticoids, PHI-induced stimulation of BFU-E progenitors thus represents a conceptually new therapeutic window for treating Epo-resistant anemia. RNA-Seq was performed on enriched populations of BFU-E, CFU-E and Ter119+ as well as BFU-E enriched cells treated with Dex and DMOG
2010-12-21 | E-GEOD-26086 | biostudies-arrayexpress