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The protein structure encoded by the FLT3 gene and the relevant pathways initiated by the activation of the FLT3 receptor. FLT3 encodes for a protein with 993 amino acids, which is a member of class III receptor tyrosine kinase family, containing an extracellular ligand binding domain, a transmembrane domain, and, intracellularly, a tyrosine kinase domain and juxtamembrane domain. ITD mutations occur in the juxtamembrane region of the receptor, which can damage its negative regulatory function, resulting in constitutive autophosphorylation of FLT3 and activation of its downstream effectors including RAS/RAF/MEK, MAPK/ERK, PI3K/AKT/mTOR and JAK/STAT5 pathways, all of which plays an important role in the promotion of cell cycle progression, cell proliferation, survival and differentiation.
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Quizartinib is an effective therapy for patients with FLT3-ITD acute myeloid leukemia (AML) by continuing to inhibit the activity of FLT3 gene, leading to apoptosis of tumor cells. Multiple clinical trials have proved that it is effective in relapsed or refractory AML with an FLT3-ITD mutation. In this review, we focus on the characteristics of FLT...
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Background:
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Citations
... Consequently, quizartinib can inhibit the growth of leukemia cells and induce apoptosis. Recent long-term clinical trials have shown that adding quizartinib to standard chemotherapy, with or without allo-HCT, and continuing monotherapy for up to three years, improves overall survival in adults aged 18-75 with newly diagnosed FLT3-ITD-positive AML [57][58][59] . Vincristine has been widely used for a long time in clinical treatment of malignant hematological tumors, including leukemia. ...
Acute Myeloid Leukemia (AML) is a malignant blood cancer with a high mortality rate. Neutrophil extracellular traps (NETs) influence various tumor outcomes. However, NET-related genes (NRGs) in AML had not yet received much attention. This study focuses on the role of NRGs in AML and their interaction with the immunological microenvironment. The gene expression and clinical data of patients with AML were downloaded from the TCGA-LAML and GEO cohorts. We identified 148 NRGs through the published article. Univariate Cox regression was used to analyze the association of NRGs with overall survival (OS). The least absolute shrinkage and selection operator were utilized to assess the predictive efficacy of NRGs. Kaplan–Meier plots visualized survival estimates. ROC curves assessed the prognostic value of NRG-based features. A nomogram, integrating clinical information and prognostic scores of patients, was constructed using multivariate logistic regression and Cox proportional hazards regression models. Twenty-seven NRGs were found to significantly impact patient OS. Six NRGs—CFTR, ENO1, PARVB, DDIT4, MPO, LDLR—were notable for their strong predictive ability regarding patient survival. The ROC values for 1-, 3-, and 5-year survival rates were 0.794, 0.781, and 0.911, respectively. In the training set (TCGA-LAML), patients in the high NRG risk group showed a poorer prognosis (p < 0.001), which was validated in two external datasets (GSE71014 and GSE106291). The 6-NRG signature and corresponding nomograms exhibit superior predictive accuracy, offering insights for pre-immune response evaluation and guiding future immuno-oncology treatments and drug selection for AML patients.
... Imidazothiazole is considered a key scaffold for developing numerous pharmacologically active molecules among broad fused heterocyclic framework 23,24 and their structural arrangement facilitates the facile binding to receptors and enzymes, resulting in synergistic biological activities such as anticancer 25 , anti-inflammatory 26 , antiviral 27 antitubercular 28 , and antimicrobial 29 . Various classes of potent biologically active imidazothiazole drugs are available in the market and are in various phases of clinical development such as levamisole, Pifthrin-β, Quizartinib, SRT1720, YM-201627, and WAY-181187 ( Fig. 1) [30][31][32][33][34][35][36] . Therefore, imidazothiazole have attracted a lot of researchers due to their potent anticancer activity. ...
A new series of imidazothiazole derivatives bearing thiazolidinone moiety (4a-g and 5a-d) were designed, synthesized and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer and anti-inflammatory activity, cardiomyopathy toxicity and hepatotoxicity. Compound 4c inhibited EGFR kinase at a concentration of 18.35 ± 1.25 µM, whereas standard drug erlotinib showed IC50 value of 06.12 ± 0.92 µM. The molecular docking, dynamics simulation and MM-GBSA binding energy calculations revealed strong interaction of compound 4c with binding site of EGFR. The synthesized compounds were evaluated for their anticancer activity by MTT assay against three human cancer cell lines A549 (Lung), MCF-7 (Breast), HCT116 (Colon), one normal human embryonic kidney cell line HEK293 and also for their EGFR kinase inhibitory activity. Few compounds of the series (4a, 4b, 4c) showed promising growth inhibition against all the tested cancer cell lines and against EGFR kinase. Among these, compound 4c was found to be most active and displayed IC50 value of 10.74 ± 0.40, 18.73 ± 0.88 against cancer cell lines A549 and MCF7 respectively whereas it showed an IC50 value of 96.38 ± 1.79 against HEK293 cell line indicating lesser cytotoxicity for healthy cell. Compounds 4a, 4b and 4c were also examined for their apoptosis inducing potential through AO/EB dual staining assay and it was observed that their antiproliferative activity against A549 cells is mediated via induction of apoptosis. Cardiomyopathy studies showed normal cardiomyocytes with no marked sign of pyknotic nucleus of compounds 4b and 4c. Hepatotoxicity studies of compounds 4b and 4c also showed normal architecture of hepatocytes. Compounds 4a-g and 5a-d were also evaluated for their in-vitro anti-inflammatory activity by protein albumin denaturation assay. Among the tested compounds 4a-d and 5a-b showed promising activity and were selected for in-vivo inflammatory activity against carrageenan rat paw edema test. Among these compounds, 4b was found to be most active in the series showing 84.94% inhibition, whereas the standard drug diclofenac sodium showed 84.57% inhibition. Compound 4b also showed low ulcerogenic potential and lipid peroxidation. Thus, compounds 4c and 4b could be a promising lead compounds for developing anticancer and anti-inflammatory agents with low toxicity and selectivity.
... Figure S4). To further test whether with conventional chemotherapy regimens [43], but also potentially relevant cardiotoxicity in clinical trials [10]. Because we previously found that Flt3 exerts protective effects in the infarcted heart through the inhibition of apoptotic cell death [27], we focused our studies on cardiomyocyte viability. ...
Background
Tyrosine kinase inhibitors (TKIs) targeting fms-like tyrosine kinase 3 (Flt3) such as quizartinib were specifically designed for acute myeloid leukemia treatment, but also multi-targeting TKIs applied to solid tumor patients inhibit Flt3. Flt3 is expressed in the heart and its activation is cytoprotective in myocardial infarction (MI) in mice.
Objectives
We sought to test whether Flt3-targeting TKI treatment aggravates cardiac injury after MI.
Methods and results
Compared to vehicle, quizartinib (10 mg/kg/day, gavage) did not alter cardiac dimensions or function in healthy mice after four weeks of therapy. Pretreated mice were randomly assigned to MI or sham surgery while receiving quizartinib or vehicle for one more week. Quizartinib did not aggravate the decline in ejection fraction, but significantly enhanced ventricular dilatation one week after infarction. In addition, apoptotic cell death was significantly increased in the myocardium of quizartinib-treated compared to vehicle-treated mice. In vitro, quizartinib dose-dependently decreased cell viability in neonatal rat ventricular myocytes and in H9c2 cells, and increased apoptosis as assessed in the latter. Together with H2O2, quizartinib potentiated the phosphorylation of the pro-apoptotic mitogen activated protein kinase p38 and augmented H2O2-induced cell death and apoptosis beyond additive degree. Pretreatment with a p38 inhibitor abolished apoptosis under quizartinib and H2O2.
Conclusion
Quizartinib potentiates apoptosis and promotes maladaptive remodeling after MI in mice at least in part via a p38-dependent mechanism. These findings are consistent with the multi-hit hypothesis of cardiotoxicity and make cardiac monitoring in patients with ischemic heart disease under Flt3- or multi-targeting TKIs advisable.
... In 2019, Quizartinib was approved as an FLT3 inhibitor in Japan for the treatment of FLT3-ITD mutated R/R AML, and recently, on 20 July 2023, the FDA approved combination of quizartinib with a "7+3" standard chemotherapy [84]. In preclinical models, quizartinib showed activity in both FLT3-ITD mutated and FLT3 wild-type line cells [85]. ...
Acute myeloid leukemia (AML) is a disease that mainly affects elderly patients who are more often unfit for intensive chemotherapy (median age of diagnosis is 68). The regimens, including venetoclax, a highly specific BCL-2 (B-cell lymphoma-2) inhibitor, are a common alternative because of their safer profile and fewer side effects. However, the resistance phenomenon of leukemic cells necessitates the search for drugs that would help to overcome the resistance and improve treatment outcomes. One of the resistance mechanisms takes place through the upregulation of MCL-1 and BCL-XL, preventing BAX/BAK-driven MOMP (mitochondrial outer membrane permeabilization), thus stopping the apoptosis process. Possible partners for BCL-2 inhibitors may include inhibitors from the FLT3i (FMS-like tyrosine kinase-3 inhibitor) group. They resensitize cancer cells through the downregulation of MCL-1 expression in the FLT3 mutated cells, resulting in the stronger efficacy of BCL-2 inhibitors. Also, they provide an additional pathway for targeting the clonal cell. Both preclinical and clinical data suggest that the combination might show a synergistic effect and improve patients’ outcomes. The aim of this review is to determine whether the combination of venetoclax and FLT3 inhibitors can impact the therapeutic approaches and what other agents they can be combined with.
... The most frequent FLT3 mutation is internal tandem repeat mutations in the proximal membrane domain, known as FLT3-ITD, which happens in about 20-25% of AML patients [8]. FLT3 mutants can induce the activation of many intracellular signaling pathways, including PI3K/AKT/mTOR, RAS/ MAPK and JAK/STAT5 signaling, which provided a proliferation/survival privilege to cancer cells [9,10]. ...
The FLT3/ITD mutation exists in many acute myeloid leukemia (AML) patients and is related to the poor prognosis of patients. In this study, we attempted to evaluate the antitumor activity of simvastatin, a member of the statin class of drugs, in vitro and in vivo models of FLT3/ITD AML and to identify the potential mechanisms.
Cell Counting Kit-8 (CCK-8) and Annexin V/propidium iodide (PI) staining kits were used to detect cell viability and apoptosis, respectively. Subsequently, Western blot and rescue experiment were applied to explore the potential molecular mechanism. In vivo anti-leukemia activity of simvastatin was evaluated in xenograft mouse models.
In vitro experiments revealed that simvastatin inhibited AML progression in a dose- and time-dependent manner, while in vivo experiments showed that simvastatin significantly reduced tumor burden in FLT3/ITD xenograft mouse models. After simvastatin treatment of FLT3/ITD AML cells, intracellular Rap1 was downregulated and the phosphorylation levels of its downstream targets MEK, ERK and p38 were significantly inhibited. The rescue experiment showed that mevalonate, an intermediate product of the metabolic pathway of mevalonate, and its downstream geranylgeranyl pyrophosphate (GGPP) played a key role in this process. Finally, we demonstrate that simvastatin can induce apoptosis of primary AML cells, while having no effect on peripheral blood mononuclear cells from normal donors.
Simvastatin can selectively and effectively eradicate FLT3/ITD AML cells in vitro and in vivo, and its mechanism may be related to the disruption of the HMG-CoA reductase pathway and the downregulation of the MEK/ERK and p38-MAPK signaling pathways.
... Gilterinib received FDA approval at the end of 2018 when the ADMIRAL study published the results of the efficacy of this next generation inhibitor against r/r FLT3-ITD AML increasing OS by 9.3 months [56,57]. It should also be mentioned how first generation inhibitors such as Sunitinib (SU11248), Midostaurin (PKC412), lestaurtinib (CEP-701), and Sorafenib (BAY43-9006) have initiated the development of new generation inhibitors such as Gilterinib, Crenolanib or Quizartinib [58,59]. The inhibitory action of monoclonal antibodies such as LY3012218 [60], a novel bispecific antibody IgG-based FLT3xCD3 for the treatment of AML [61], is also studied. ...
Acute myeloid leukemia (AML) is a malignant blood cancer with marked cellular heterogeneity due to altered maturation and differentiation of myeloid blasts, the possible causes of which are transcriptional or epigenetic alterations, impaired apoptosis, and excessive cell proliferation. This neoplasm has a high rate of resistance to anticancer therapies and thus a high risk of relapse and mortality because of both the biological diversity of the patient and intratumoral heterogeneity due to the acquisition of new somatic changes. For more than 40 years, the old gold standard “one size fits all” treatment approach included intensive chemotherapy treatment with anthracyclines and cytarabine.
The manuscript first traces the evolution of the understanding of the pathology from the 1970s to the present. The enormous strides made in its categorization prove to be crucial for risk stratification, enabling an increasingly personalized diagnosis and treatment approach.
Subsequently, we highlight how, over the past 15 years, technological advances enabling single cell RNA sequencing and T-cell modification based on the genomic tools are affecting the classification and treatment of AML. At the dawn of the new millennium, the advent of high-throughput next-generation sequencing technologies has enabled the profiling of patients evidencing different facets of the same disease, stratifying risk, and identifying new possible therapeutic targets that have subsequently been validated. Currently, the possibility of investigating tumor heterogeneity at the single cell level, profiling the tumor at the time of diagnosis or after treatments exist. This would allow the identification of underrepresented cellular subclones or clones resistant to therapeutic approaches and thus responsible for post-treatment relapse that would otherwise be difficult to detect with bulk investigations on the tumor biopsy. Single-cell investigation will then allow even greater personalization of therapy to the genetic and transcriptional profile of the tumor, saving valuable time and dangerous side effects. The era of personalized medicine will take a huge step forward through the disclosure of each individual piece of the complex puzzle that is cancer pathology, to implement a “tailored” therapeutic approach based also on engineered CAR-T cells.
... Mutations cause constant activation of the FLT3 pathway resulting in inhibition of ligand-independent leukemic cell proliferation and apoptosis. Good results were obtained in a phase II clinical trial in 2012 for refractory AML, especially in patients undergoing stem cell transplantation [106]. ...
Imidazothiazole derivatives are becoming increasingly important in therapeutic use due to their outstanding physiological activities. Recently, applying imidazothiazole as the core, researchers have synthesized a series of derivatives with biological effects such as antitumor, anti-infection, anti-inflammatory and antioxidant effects. In this review, we summarize the main pharmacological effects and pharmacological mechanisms of imidazothiazole derivates; the contents summarized herein are intended to advance the research and rational development of imidazothiazole-based drugs in the future.
... 54,55 Quizartinib, an FLT3 inhibitor, showed excellent efficacy and induced complete remission in FLT3-mutant AML tumors. 56 However, FLT3 expression was associated with a good prognosis in neuroblastoma, and whether a mutation of FLT3 exists in neuroblastoma is not known. [57][58][59] We found that FLT3 seems to be a cancer-protective gene in neuroblastoma, that is upregulated and associated with a favorable outcome. ...
Introduction:
Neuroblastoma is the most common extracranial solid tumor in children. Patients with high-risk neuroblastoma have a 5-year survival rate less than 50% after extensive treatment. Signaling pathways control cell fate decisions that dictate the behavior of tumor cells. The deregulation of signaling pathways is etiological in cancer cells. Thus, we speculated that the pathway activity of neuroblastoma contains more prognostic information and therapeutic targets.
Methods:
Using a footprint-based method, we calculated the activity of fourteen pathways in neuroblastoma. Through stepwise Cox regression analyses, we established a three-gene prognostic signature whose predictive performance was evaluated by external validation. Combining a single-cell sequencing dataset, the most active pathways in high-risk neuroblastoma were found.
Results:
We found that several pathway activities were correlated with neuroblastoma outcomes. We built a three-gene model comprising DLK1, FLT3, and NTRK1, which exhibited superior internal and external performances. We created a nomogram that combines clinical characteristics to aid in the selection and visualization of high-risk neuroblastoma patients. Furthermore, by integrating a single-cell sequencing dataset, we found that estrogen and MAPK were the most active pathways in high-risk neuroblastoma.
Conclusion:
Our findings suggest that pathway-related therapies may hold promise for the treatment of high-risk neuroblastoma.
... The most common genetic abnormality, present in around 30% of cases, is the alteration of the FMS-type tyrosine kinase 3 gene (FLT3), either in the form of point mutations or internal tandem duplication (ITD), which have been associated with a poor prognosis [141]. Therefore, treatments with TKIs and strategies modulating the expression of FLT3-ITD constitute promising approaches [142,143]. Furthermore, AML samples with this type of mutation have been shown to be more sensitive to proteasome inhibitors (PIs) [144]. PIs have been shown to be capable of overcoming resistance to quizartinib (a secondgeneration ITQ), induced by mutations in the kinase domain of FLT3, suggesting that the combined application of both drugs may produce favorable results. ...
Autophagy is a highly conserved metabolic pathway by which the intracellular unwanted materials, such as unfolded proteins or damaged organelles, are digested. It is activated in response to conditions of oxidative stress or starvation, and it is essential for the maintenance of cellular homeostasis and other vital functions, such as differentiation, cell death and cell cycle. Therefore, autophagy plays an important role in the initiation and progression of tumors, including hematological malignancies, where damaged autophagy during hematopoiesis can cause malignant transformation and increase cell proliferation. Over the last decade, the importance of autophagy in the response to standard pharmacological treatment of hematological tumors has been observed, revealing completely opposite roles depending on the tumor type and tumor stage. Thus, autophagy can promote tumor survival by attenuating cellular damage caused by drugs and/or stabilizing oncogenic proteins, but it can also have an antitumoral effect due to autophagic cell death. Therefore, autophagy-based strategies must depend on the context to create specific and safe combination therapies that could contribute to improve clinical outcomes. In this review, we describe the process of autophagy, its role on hematopoiesis and we highlight recent research investigating its role as potential therapeutic target in hematological malignancies and the findings suggesting that genetic variants within autophagy-related genes modulate the risk of developing hemopathies as well as patient survival.
... Our results showed that the sensitivity to ATRA was negatively correlated with the expression of CD33, siglec5, siglec9 and siglec12 (FDR ≤ 0.05). AC220 is a selective inhibitor of FLT3 [30] and is shown to be effective in relapsed or refractory AML with FLT3-ITD mutation [31]. We found that the expression levels of CD33, siglec5, siglec9 and siglec12 were negatively correlated with the sensitivity to AC220 (FDR ≤ 0.05). ...
Background
Acute myeloid leukemia (AML) is a group of highly heterogenous and aggressive blood cancer. Despite recent progress in its diagnosis and treatment, patient outcome is variable and drug resistance results in increased mortality. The siglec family plays an important role in tumorigenesis and aging. Increasing age is a risk factor for AML and cellular aging contributes to leukemogenesis via various pathways.
Methods
The differential expression of the siglec family was compared between 151 AML patients and 70 healthy controls, with their information downloaded from TCGA and GTEx databases, respectively. How siglec expression correlated to AML patient clinical features, immune cell infiltration, drug resistance and survival outcome was analyzed. Differentially expressed genes in AML patients with low- and high-expressed siglec9 and siglec14 were analyzed and functionally enriched. The aging-related gene set was merged with the differentially expressed genes in AML patients with low and high expression of siglec9, and merged genes were subjected to lasso regression analysis to construct a novel siglec-based and aging-related prognostic model. The prediction model was validated using a validation cohort from GEO database (GSE106291).
Results
The expression levels of all siglec members were significantly altered in AML. The expression of siglecs was significantly correlated with AML patient clinical features, immune cell infiltration, drug resistance, and survival outcome. Based on the differentially expressed genes and aging-related gene set, we developed a 9-gene prognostic model and decision curve analysis revealed the net benefit generated by our prediction model. The siglec-based and aging-related 9-gene prognostic model was tested using a validation data set, in which AML patients with higher risk scores had significantly reduced survival probability. Time-dependent receiver operating characteristic curve and nomogram were plotted and showed the diagnostic accuracy and predictive value of our 9-gene prognostic model, respectively.
Conclusions
Overall, our study indicates the important role of siglec family in AML and the good performance of our novel siglec-based and aging-related 9-gene signature in predicting AML patient outcome.
