Asunto(s)
Sinergismo Farmacológico , Leucemia Mieloide Aguda , Mutación , Inhibidores de Proteínas Quinasas , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Quinasa Activadora de Quinasas Ciclina-Dependientes , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
A 72-year-old woman with relapsed FLT3-ITD-positive acute myeloid leukemia was treated with gilteritinib and achieved complete remission with incomplete hematological recovery. However, two months later, she developed optic nerve infiltration and lost vision in her right eye while maintaining hematological remission on gilteritinib. Intrathecal injection of cytotoxic drugs reduced the number of blasts in the cerebrospinal fluid (CSF), but her vision did not recover. At the onset of optic nerve infiltration, at a dose of 80 mg/day gilteritinib, the plasma trough and CSF levels of gilteritinib were 151.9 ng/ml and 1.9 ng/ml, respectively, with a central nervous system (CNS) penetration rate of 1.3%. Hematologic progressive disease (PD) was detected after 40 days, and the patient died one month later. Target sequencing at the time of hematologic PD revealed the FLT3 F691L mutation, which is known to confer resistance to gilteritinib. In this patient, pharmacokinetic (low CNS penetration of gilteritinib) and pharmacodynamic (acquisition of a drug resistance mutation) mechanisms were thought to be responsible for the CNS relapse and hematologic PD, respectively. We believe this is a valuable case to report considering the scarcity of data on CNS penetration of FLT3 inhibitors and their effects on CNS disease in the literature.
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Compuestos de Anilina , Leucemia Mieloide Aguda , Pirazinas , Recurrencia , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Pirazinas/administración & dosificación , Pirazinas/uso terapéutico , Anciano , Femenino , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/administración & dosificación , Tiofenos/administración & dosificación , Tiofenos/uso terapéutico , Nervio Óptico/patología , Mutación , Resultado FatalRESUMEN
FMS-like tyrosine kinase 3 (FLT3) mutations are genetic changes found in approximately thirty percent of patients with acute myeloid leukemia (AML). FLT3 mutations in AML represent a challenging clinical scenario characterized by a high rate of relapse, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The advent of FLT3 tyrosine kinase inhibitors (TKIs), such as midostaurin and gilteritinib, has shown promise in achieving complete remission. However, a substantial proportion of patients still experience relapse following TKI treatment, necessitating innovative therapeutic strategies. This review critically addresses the current landscape of TKI treatments for FLT3+ AML, with a particular focus on gilteritinib. Gilteritinib, a highly selective FLT3 inhibitor, has demonstrated efficacy in targeting the mutant FLT3 receptor, thereby inhibiting aberrant signaling pathways that drive leukemic proliferation. However, monotherapy with TKIs may not be sufficient to eradicate AML blasts. Specifically, we provide evidence for integrating gilteritinib with mammalian targets of rapamycin (mTOR) inhibitors and interleukin-15 (IL-15) complexes. The combination of gilteritinib, mTOR inhibitors, and IL-15 complexes presents a compelling strategy to enhance the eradication of AML blasts and enhance NK cell killing, offering a potential for improved patient outcomes.
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Leucemia Mieloide Aguda , Inhibidores de Proteínas Quinasas , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pirazinas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Mutación , Transducción de Señal/efectos de los fármacos , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/farmacologíaRESUMEN
Activating FLT3 mutations plays a crucial role in leukemogenesis, but identifying the optimal candidates for FLT3 inhibitor therapy remains controversial. This study aims to explore the impacts of FLT3 mutations in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and to compare the mutation profiles between the two types to inspire the targeted application of FLT3 inhibitors. We retrospectively analyzed 243 ALL and 62 AML cases, grouping them into FLT3-mutant and wild-type categories, respectively. We then assessed the associations between FLT3 mutations and the clinical manifestations, genetic characteristics, and prognosis in ALL and AML. Additionally, we compared the distinct features of FLT3 mutations between ALL and AML. In ALL patients, those with FLT3 mutations predominantly exhibited hyperdiploidy (48.6% vs. 14.9%, p < 0.001) and higher FLT3 expression (108.02 [85.11, 142.06] FPKM vs. 23.11 [9.16, 59.14] FPKM, p < 0.001), but lower expression of signaling pathway-related genes such as HRAS, PIK3R3, BAD, MAP2K2, MAPK3, and STAT5A compared to FLT3 wild-type patients. There was no significant difference in prognosis between the two groups. In contrast, AML patients with FLT3 mutations were primarily associated with leucocytosis (82.90 [47.05, 189.76] G/L vs. 20.36 [8.90, 55.39] G/L, p = 0.001), NUP98 rearrangements (30% vs. 4.8%, p = 0.018), elevated FLT3 expression (74.77 [54.31, 109.46] FPKM vs. 34.56 [20.98, 48.28] FPKM, p < 0.001), and upregulated signaling pathway genes including PIK3CB, AKT1, MTOR, BRAF, and MAPK1 relative to FLT3 wild-type, correlating with poor prognosis. Notably, internal tandem duplications were the predominant type of FLT3 mutation in AML (66.7%) with higher inserted base counts, whereas they were almost absent in ALL (6.3%, p < 0.001). In summary, our study demonstrated that the forms and impacts of FLT3 mutations in ALL differed significantly from those in AML. The gene expression profiles of FLT3-related pathways may provide a rationale for using FLT3 inhibitors in AML rather than ALL when FLT3 mutations are present.
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Leucemia Mieloide Aguda , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Niño , Masculino , Femenino , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Preescolar , Pronóstico , Transcriptoma , Lactante , Adolescente , Estudios Retrospectivos , Transducción de Señal/genética , Terapia Molecular Dirigida , Regulación Leucémica de la Expresión Génica/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate the clinical characteristics and influence of co-mutated gene on acute myeloid leukemia patients (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. METHODS: A total of 273 FLT3+ AML patients were enrolled, and the co-mutation gene data of the patients were collected to further analyze the prognosis of the patients. FLT3 and other common mutations were quantified by PCR amplification products direct sequencing and second-generation sequencing (NGS). RESULTS: When patients were divided into FLT3- ITD +, FLT3- TKD +, FLT3- ITD ++TKD + and FLT3- ITD -+TKD - group according to the type of FLT3 mutations, it was found that the frequencies of TET2, GATA2, NRAS and ASXL1 mutation were significantly different among the 4 groups (all P < 0.05). When patients were divided into allelic ratio (AR) ≥0.5 and <0.5 group, it was found that the frequencies of FLT3- ITD +, FLT3 -ITD - +TKD -, NPM1, NRAS and C-kit were significantly different between the two groups (all P < 0.05). When patients were divided into normal and abnormal karyotype group, it was found that the frequencies of FLT3- ITD +, FLT3- TKD +, NPM1, GATA2 and C-kit were significantly different between the two groups (all P < 0.05). The median overall survival (OS) of AML patients with FLT3 -TKD + (including FLT3- ITD ++TKD +) was longer than that of patients with FLT3- ITD + alone (P < 0.05). The OS and relapse-free survival (RFS) of AML patients with FLT3++TET2+ were both shorter than those of patients with FLT3++TET2- (both P < 0.05). CONCLUSION: The mutation frequencies of co-mutated genes are correlated with subtypes of FLT3, karyotype and AR. AML patients with FLT3 -TKD + have longer OS than patients with FLT3- ITD + alone, and patients with co-mutation of TET2 have shorter median OS and RFS.
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Dioxigenasas , GTP Fosfohidrolasas , Leucemia Mieloide Aguda , Mutación , Nucleofosmina , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Leucemia Mieloide Aguda/genética , Pronóstico , GTP Fosfohidrolasas/genética , Proteínas de Unión al ADN/genética , Factor de Transcripción GATA2/genética , Proteínas Represoras/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-kit/genéticaRESUMEN
OBJECTIVE: To investigate the expression and clinical significance of long noncoding RNA(lncRNA) HEIH in patients with acute myeloid leukemia (AML). METHODS: 50 newly diagnosed AML patients (except M3) admitted to the First Affiliated Hospital of Bengbu Medical College from January 2019 to December 2020 were included in the study, with 30 patients with non-hematological malignancies as controls. The relative expression level of lncRNA HEIH in all patients were detected, the correlation of clinical characteristics, gene mutations, FAB classification, efficacy, prognosis and overall survival (OS) of AML patients with the expression level of lncRNA HEIH were analyzed. RESULTS: The expression level of lncRNA HEIH in AML patients was significantly higher than that in patients with non-hematological malignancies (P <0.01). Moreover, AML patients with high white blood cell count (WBC), CEBPA and FLT3 mutations, poor efficacy, and poor prognosis often showed higher expression of lncRNA HEIH, and patients with high lncRNA HEIH expression showed a shorter overall survival (OS). CONCLUSION: lncRNA HEIH shows an unique molecular biological significance in AML patients, which may provide a new approach for diagnosis, monitoring and targeted therapy of AML.
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Leucemia Mieloide Aguda , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Leucemia Mieloide Aguda/genética , Pronóstico , Mutación , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Tirosina Quinasa 3 Similar a fms/genética , Masculino , Relevancia ClínicaRESUMEN
Next-generation sequencing of samples from patients with acute myeloid leukemia (AML) has revealed several driver gene mutations in adult AML. However, unlike other cancers, AML is defined by relatively few mutations per patient, with a median of 4-5 depending on subtype. In this review, we will discuss the most common driver genes found in patients with AML and focus on the most clinically relevant ones that impact treatment strategies. The most common driver gene mutations in AML occur in NPM1 and FLT3, accounting for ~30% each. There are now targeted therapies being tested or already approved for these driver genes. Menin inhibitors, a novel targeted therapy that blocks the function of the menin protein, are in clinical trials for NPM1 driver gene mutant AML after relapse. A number of FLT3 inhibitors are now approved for FLT3 driver gene mutant AML in combination with chemotherapy in the frontline and also as single agent in relapse. Although mutations in IDH1/2 and TP53 only occur in around 10-20% of patients with AML each, they can affect the treatment strategy due to their association with prognosis and availability of targeted agents. While the impact of other driver gene mutations in AML is recognized, there is a lack of data on the actionable impact of those mutations.
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Leucemia Mieloide Aguda , Mutación , Nucleofosmina , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación/genética , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/metabolismo , Terapia Molecular DirigidaRESUMEN
OBJECTIVE: Patients who carry NUP98::NSD1 or FLT3/ITD mutations are reported to have poor prognosis. Previous studies have confidently reported that the poor outcome in younger AML patients is owning to dual NUP98::NSD1 and FLT3/ITD positivity, with a high overlap for those two genetic lesions. In this study, we assessed the prognostic value of the presence of both NUP98::NSD1 and FLT3/ITD in pediatric AML patients. METHODS: We screened a large cohort of 885 pediatric cases from the COG-National Cancer Institute (NCI) TARGET AML cohort and found 57 AML patients with NUP98 rearrangements. RESULTS: The frequency of NUP98 gene fusion was 10.8% in 529 patients. NUP98::NSD1 fusion was the most common NUP98 rearrangement, with a frequency of 59.6%(34 of 57). NUP98::NSD1 -positive patients who carried FLT3/ITD mutations had a decreased CR1 or CR2 rate than those patients carried FLT3/ITD mutation alone (P = 0.0001). Moreover, patients harboring both NUP98::NSD1 fusion and FLT3/ITD mutation exhibited inferior event-free survival (EFS, P < 0.001) and overall survival (OS, P = 0.004) than patients who were dual negative for these two genetic lesions. The presence of only NUP98::NSD1 fusion had no significant impact on EFS or OS. We also found that cases with high FLT3/ITD AR levels ( > = 0.5) with or without NUP98::NSD1 had inferior prognosis. Multivariate analysis demonstrated that the presence of both NUP98::NSD1 and FLT3/ITD was an independent prognostic factors for EFS (hazard ratio: 3.2, P = 0.001) in patients with pediatric AML. However, there was no obvious correlation with OS (hazard ratio: 1.3, P = 0.618). Stem cell transplantation did not improve the survival rate of cases with NUP98 fusion or NUP98::NSD1 AML in terms of EFS or OS. CONCLUSION: Presence of both NUP98::NSD1 and FLT3/ITD was found to be an independent factor for dismal prognosis in pediatric AML patients. Notably, lack of FLT3/ITD mutations in NUP98::NSD1 -positive patients did not retain its prognostic value.
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Leucemia Mieloide Aguda , Mutación , Proteínas de Complejo Poro Nuclear , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Niño , Femenino , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Pronóstico , Preescolar , Proteínas de Complejo Poro Nuclear/genética , Adolescente , Lactante , Proteínas de Fusión Oncogénica/genética , N-Metiltransferasa de Histona-Lisina/genética , Proteínas Nucleares/genética , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
BACKGROUND: Nucleophosmin 1 (NPM1) gene-mutated acute myeloid leukemia (NPM1mut AML) is classified as a subtype with a favorable prognosis. However, some patients fail to achieve a complete remission or relapse after intensified chemotherapy. Genetic abnormalities in concomitant mutations contribute to heterogeneous prognosis of NPM1mut AML patients. METHODS: In this study, 91 NPM1-mutated and FLT3-ITD wild-type (NPM1mut/FLT3-ITDwt) AML patients with intermediate-risk karyotype were enrolled to analyze the impact of common genetic co-mutations on chemotherapeutic outcome. RESULTS: Our data revealed that TET1/2 (52/91, 57.1%) was the most prevalent co-mutation in NPM1mut AML patients, followed by IDH1/2 (36/91, 39.6%), DNMT3A (35/91, 38.5%), myelodysplastic syndrome related genes (MDS-related genes) (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 genes) (35/91, 38.5%), FLT3-TKD (27/91, 29.7%) and GATA2 (13/91, 14.3%) mutations. Patients with TET1/2mut exhibited significantly worse relapse-free survival (RFS) (median, 28.7 vs. not reached (NR) months; p = 0.0382) compared to patients with TET1/2wt, while no significant difference was observed in overall survival (OS) (median, NR vs. NR; p = 0.3035). GATA2mut subtype was associated with inferior OS (median, 28 vs. NR months; p < 0.0010) and RFS (median, 24 vs. NR months; p = 0.0224) compared to GATA2wt. By multivariate analysis, GATA2mut and MDS-related genesmut were independently associated with worse survival. CONCLUSION: Mutations in TET1/2, GATA2 and MDS-related genes were found to significantly influence the chemotherapeutic outcome of patients with NPM1mut AML. The findings of our study have significant clinical implications for identifying patients who have an adverse response to frontline chemotherapy and provide a novel reference for further prognostic stratification of NPM1mut/FLT3-ITDwt AML patients.
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Leucemia Mieloide Aguda , Mutación , Proteínas Nucleares , Nucleofosmina , Tirosina Quinasa 3 Similar a fms , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Adulto , Tirosina Quinasa 3 Similar a fms/genética , Anciano , Pronóstico , Adulto Joven , Resultado del Tratamiento , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: Approximately 25-30% of patients with acute myeloid leukemia (AML) have FMS-like receptor tyrosine kinase-3 (FLT3) mutations that contribute to disease progression and poor prognosis. Prolonged exposure to FLT3 tyrosine kinase inhibitors (TKIs) often results in limited clinical responses due to diverse compensatory survival signals. Therefore, there is an urgent need to elucidate the mechanisms underlying FLT3 TKI resistance. Dysregulated sphingolipid metabolism frequently contributes to cancer progression and a poor therapeutic response. However, its relationship with TKI sensitivity in FLT3-mutated AML remains unknown. Thus, we aimed to assess mechanisms of FLT3 TKI resistance in AML. METHODS: We performed lipidomics profiling, RNA-seq, qRT-PCR, and enzyme-linked immunosorbent assays to determine potential drivers of sorafenib resistance. FLT3 signaling was inhibited by sorafenib or quizartinib, and SPHK1 was inhibited by using an antagonist or via knockdown. Cell growth and apoptosis were assessed in FLT3-mutated and wild-type AML cell lines via Cell counting kit-8, PI staining, and Annexin-V/7AAD assays. Western blotting and immunofluorescence assays were employed to explore the underlying molecular mechanisms through rescue experiments using SPHK1 overexpression and exogenous S1P, as well as inhibitors of S1P2, ß-catenin, PP2A, and GSK3ß. Xenograft murine model, patient samples, and publicly available data were analyzed to corroborate our in vitro results. RESULTS: We demonstrate that long-term sorafenib treatment upregulates SPHK1/sphingosine-1-phosphate (S1P) signaling, which in turn positively modulates ß-catenin signaling to counteract TKI-mediated suppression of FLT3-mutated AML cells via the S1P2 receptor. Genetic or pharmacological inhibition of SPHK1 potently enhanced the TKI-mediated inhibition of proliferation and apoptosis induction in FLT3-mutated AML cells in vitro. SPHK1 knockdown enhanced sorafenib efficacy and improved survival of AML-xenografted mice. Mechanistically, targeting the SPHK1/S1P/S1P2 signaling synergizes with FLT3 TKIs to inhibit ß-catenin activity by activating the protein phosphatase 2 A (PP2A)-glycogen synthase kinase 3ß (GSK3ß) pathway. CONCLUSIONS: These findings establish the sphingolipid metabolic enzyme SPHK1 as a regulator of TKI sensitivity and suggest that combining SPHK1 inhibition with TKIs could be an effective approach for treating FLT3-mutated AML.
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Glucógeno Sintasa Quinasa 3 beta , Leucemia Mieloide Aguda , Fosfotransferasas (Aceptor de Grupo Alcohol) , Proteína Fosfatasa 2 , beta Catenina , Tirosina Quinasa 3 Similar a fms , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , beta Catenina/metabolismo , beta Catenina/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Animales , Ratones , Proteína Fosfatasa 2/metabolismo , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/antagonistas & inhibidores , Línea Celular Tumoral , Sorafenib/farmacología , Apoptosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genéticaRESUMEN
The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory (R/R) FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but the overall survival (OS) is only approximately 20â¯% and few patients achieve deep and/ or durable response. We retrospectively analyzed 29â¯R/R FLT3mut AML patients treated on triplet regimens (gilteritinib+ venetoclaxï¼»VEN] +azacitidineï¼»AZA]). Nineteen patients (65.5â¯%) had received prior FLT3 inhibitor therapy. The modified composite complete remission (mCRc) rate was 62.1â¯% (n = 18; CR, 4/29,13.8â¯%; CRi, 6/29, 20.7â¯%; MLFS, 8/29, 27.6â¯%). Among 18 patients achieved mCRc, FLT3-PCR negativity was 94.4â¯% (n=17), and flow-cytometry negativity was 77.7â¯% (n=14). The mCRc rate was 70â¯% (n=7) in 10 patients without prior FLT3 TKI exposure and 57.8â¯% (n=11) in 19 patients with prior FLT3 TKI exposure (P=0.52). At the end of the first cycle, the median time to ANC > 0.5× 109/L was 38 days and platelet > 50× 109/L was 31 days among responders, but 60-day mortality was 0â¯%. The estimated 2-year OS was 60.9â¯% for all R/R FLT3mut patients. The 1-year OS was 80â¯% and 58.8â¯% in patients without and with prior FLT3 TKI exposure, respectively (P=0.79). The estimated 2-year OS was 62â¯% in 19 (65.5â¯%) patients who received allo-HSCT after triplet therapy and 37â¯% in 10 patients who did not receive allo-HSCT (P=0.03). In conclusion, triplet therapy with gilteritinib, VEN, and AZA is effective and safe and an excellent frontline option for R/R FLT3mut AML.
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Compuestos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Pirazinas , Sulfonamidas , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Masculino , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/genética , Femenino , Persona de Mediana Edad , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Estudios Retrospectivos , Compuestos de Anilina/uso terapéutico , Adulto , Pirazinas/uso terapéutico , Pirazinas/administración & dosificación , Azacitidina/uso terapéutico , Azacitidina/administración & dosificación , Mutación , Tiofenos/uso terapéutico , Tiofenos/administración & dosificación , Resistencia a AntineoplásicosRESUMEN
The urgent and unmet medical demand of acute myeloid leukemia (AML) patients has driven the drug discovery process for expansion of the landscape of AML treatment. Despite the several agents developed for treatment of AML, more than 60 % of treated patients undergo relapse again after re-emission, thus, no complete cure for this complex disease has been reached yet. Targeted oncoprotein degradation is a new paradigm that can be employed to solve drug resistance, disease relapse, and treatment failure in complex diseases as AML, the most lethal hematological malignancy. AML is an aggressive blood cancer form and the most common type of acute leukemia, with bad outcomes and a very poor 5-year survival rate. FLT3 mutations occur in about 30 % of AML cases and FLT3-ITD is associated with poor prognosis of this disease. Prevalent FLT3 mutations include internal tandem duplication and point mutations (e.g., D835) in the tyrosine kinase domain, which induce FLT3 kinase activation and result in survival and proliferation of AML cells again. Currently approved FLT3 inhibitors suffer from limited clinical efficacy due to FLT3 reactivation by mutations, therefore, alternative new treatments are highly needed. Proteolysis-targeting chimera (PROTAC) is a bi-functional molecule that consists of a ligand of the protein of interest, FLT3 inhibitor in our case, that is covalently linked to an E3 ubiquitin ligase ligand. Upon FLT3-specific PROTAC binding to FLT3, the PROTAC can recruit E3 for FLT3 ubiquitination, which is subsequently subjected to proteasome-mediated degradation. In this review we tried to address the question if PROTAC technology has succeeded in tackling the disease relapse and treatment failure of AML. Next, we explored the latest FLT3-targeting PROTACs developed in the past few years such as quizartinib-based PROTACs, dovitinib-based PROTACs, gilteritinib-based PROTACs, and others. Then, we followed with a deep analysis of their advantages regarding potency improvement and overcoming AML drug resistance. Finally, we discussed the challenges facing these chimeric molecules with proposed future solutions to circumvent them.
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Antineoplásicos , Leucemia Mieloide Aguda , Inhibidores de Proteínas Quinasas , Tirosina Quinasa 3 Similar a fms , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/metabolismo , Tirosina Quinasa 3 Similar a fms/genética , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Resistencia a Antineoplásicos/efectos de los fármacos , Proteolisis/efectos de los fármacos , Estructura Molecular , Quimera Dirigida a la ProteólisisRESUMEN
FLT3 mutation is one of the most frequent genetic mutations in AML, identified in approximately 30% of patients, and FLT3-ITD mutation is considered a poor prognostic factor. Based on these molecular and clinical backgrounds, FLT3 mutations are considered promising therapeutic targets in AML, and intensive development of targeted therapeutics has been ongoing for more than two decades. Recently, combination of FLT3 inhibitors with intensive chemotherapy for untreated AML patients with FLT3 mutations and FLT3 inhibitor monotherapy for relapsed/refractory patients have been approved. In Japan, the combination of quizartinib and intensive chemotherapy for untreated FLT3-ITD-positive AML was approved in 2023. Clinical use of FLT3 inhibitors shows strong promise for improving the clinical outcomes of these AML patients with an extremely poor prognosis. Meanwhile, various resistance mechanisms to FLT3 inhibitors have been identified, including the emergence of resistance-associated mutations, and attenuated inhibitory effects of FLT3 inhibitors involving the bone marrow microenvironment surrounding AML cells. Thus, future efforts should aim to optimize combination therapy based on the characteristics of each FLT3 inhibitor, develop biomarkers that could inform treatment selection, and to better understand these resistance mechanisms and develop methods for overcoming them.
Asunto(s)
Leucemia Mieloide Aguda , Mutación , Inhibidores de Proteínas Quinasas , Tirosina Quinasa 3 Similar a fms , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Resistencia a AntineoplásicosRESUMEN
Fms-like tyrosine kinase 3 (FLT3) mutations, present in over 30% of acute myeloid leukemia (AML) cases and dominated by FLT3-internal tandem duplication (FLT3-ITD), are associated with poor outcomes in patients with AML. While tyrosine kinase inhibitors (TKIs; e.g., gilteritinib) are effective, they face challenges such as drug resistance, relapse, and high costs. Here, we report that metformin, a cheap, safe, and widely used anti-diabetic agent, exhibits a striking synergistic effect with gilteritinib in treating FLT3-ITD AML. Metformin significantly sensitizes FLT3-ITD AML cells (including TKI-resistant ones) to gilteritinib. Metformin plus gilteritinib (low dose) dramatically suppresses leukemia progression and prolongs survival in FLT3-ITD AML mouse models. Mechanistically, the combinational treatment cooperatively suppresses polo-like kinase 1 (PLK1) expression and phosphorylation of FLT3/STAT5/ERK/mTOR. Clinical analysis also shows improved survival rates in patients with FLT3-ITD AML taking metformin. Thus, the metformin/gilteritinib combination represents a promising and cost-effective treatment for patients with FLT3-mutated AML, particularly for those with low income/affordability.
Asunto(s)
Compuestos de Anilina , Proteínas de Ciclo Celular , Sinergismo Farmacológico , Leucemia Mieloide Aguda , Metformina , Mutación , Quinasa Tipo Polo 1 , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Pirazinas , Transducción de Señal , Tirosina Quinasa 3 Similar a fms , Metformina/farmacología , Metformina/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Humanos , Animales , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Transducción de Señal/efectos de los fármacos , Pirazinas/farmacología , Pirazinas/uso terapéutico , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Ratones , Mutación/genética , Línea Celular Tumoral , Tiofenos/farmacología , Tiofenos/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Factor de Transcripción STAT5/metabolismo , Factor de Transcripción STAT5/genética , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
INTRODUCTION: Acute myeloid leukemia with normal cytogenetics (CN-AML) represents a heterogeneous group having diverse genetic mutations. Understanding the significance of each of these mutations is necessary. In this study, we evaluated the prognostic role of MN1 expression in adult CN-AML patients. METHOD: One hundred and sixty-three de-novo adult AML patients were evaluated for MN1 expression by real-time PCR. MN1 expression was correlated with the clinical characteristics of the patients and their outcomes. RESULTS: Higher MN1 expression was associated with NPM1 wild-type (p<0.0001), CD34 positivity (p=0.006), and lower clinical remission rate (p=0.027). FLT3-ITD and CEBPA mutations had no association with MN1 expression. On survival analysis, a high MN1 expression was associated with poor event-free survival (Hazard Ratio 2.47, 95% Confidence Interval: 1.42-4.3; p<0.0001) and overall survival (Hazard Ratio 4.18, 95% Confidence Interval: 2.17-8.08; p<0.0001). On multivariate analysis, the MN1 copy number emerged as an independent predictor of EFS (p<0.0001) and OS (p<0.0001). CONCLUSION: MN1 expression is an independent predictor of outcome in CN-AML.
Asunto(s)
Biomarcadores de Tumor , Leucemia Mieloide Aguda , Nucleofosmina , Transactivadores , Proteínas Supresoras de Tumor , Humanos , Masculino , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Femenino , Adulto , Persona de Mediana Edad , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Pronóstico , Adulto Joven , Transactivadores/genética , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Tasa de Supervivencia , Estudios de Seguimiento , Adolescente , Mutación , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Medición de Riesgo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Anciano de 80 o más AñosRESUMEN
FLT3 inhibitors combined with chemotherapy are the standard of care for newly diagnosed FLT3-mutated acute myeloid leukemia (AML). However, no head-to-head studies have established the superiority of one FLT3 inhibitor over another. We conducted a network meta-analysis (NMA) to evaluate overall survival (OS) among different FLT3 inhibitors. Three relevant randomized controlled trials (RCTs), involving 1.358 patients treated with midostaurin, quizartinib, and sorafenib, were included in our analysis. The hazard ratios (HRs) revealed no significant differences in OS between midostaurin and quizartinib (HR, 1.00; 95â¯% CI, 0.73-1.36), midostaurin and sorafenib (HR, 0.97; 95â¯% CI, 0.52-1.84), or quizartinib and sorafenib (HR, 0.97; 95â¯% CI, 0.51-1.85). This NMA, the first to explore this issue, found no OS differences among the different FLT3 inhibitors. In the absence of direct comparison trials, our findings provide practical insights for clinical decision-making.
Asunto(s)
Leucemia Mieloide Aguda , Metaanálisis en Red , Inhibidores de Proteínas Quinasas , Sorafenib , Estaurosporina , Tirosina Quinasa 3 Similar a fms , Humanos , Benzotiazoles/uso terapéutico , Benzotiazoles/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Sorafenib/uso terapéutico , Estaurosporina/análogos & derivados , Estaurosporina/uso terapéutico , Tasa de SupervivenciaRESUMEN
We present a case of a patient diagnosed with FLT3 mut+ acute myeloid leukemia with FLT3 and NMP1 mutations who did not respond to standard induction and consolidation treatment with chemotherapy. Due to the FLT3mut+ gene mutation and intermediate cytogenetic risk, treatment with gilteritinib is requested. After treatment she experienced a neutrophilic dermatosis and granuloma annulare that was resolved with gilteritinib dose reduction and specific treatment in coordination with the dermatology department.
Asunto(s)
Compuestos de Anilina , Leucemia Mieloide Aguda , Mutación , Pirazinas , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Pirazinas/efectos adversos , Pirazinas/uso terapéutico , Femenino , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/efectos adversos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Persona de Mediana EdadRESUMEN
Cluster of differentiation 99 (CD99) is a receptor that is significantly upregulated in acute myeloid leukemia (AML). FMS-like tyrosine kinase 3 internal tandem duplication mutation in AML (FLT3-ITD AML) exhibits even higher levels of CD99 expression. Our group previously employed a novel peptide platform technology called elastin-like polypeptides and fused it with single-chain antibodies capable of binding to FLT3 (FLT3-A192) or CD99 (CD99-A192). Targeting either FLT3 or CD99 using FLT3-A192 or CD99-A192 led to AML cell death and reduced leukemia burden in AML mouse models. Here, we report on the development of a novel Co-Assembled construct that is capable of binding to both CD99 and FLT3 and the antileukemia activity of the bispecific construct in FLT3-ITD AML preclinical models. This dual-targeting Co-Assembled formulation exhibits cytotoxic effects on AML cells (AML cell lines and primary blasts) and reduced leukemia burden and prolonged survival in FLT3-ITD AML mouse models. Altogether, this study demonstrates the potential of an innovative therapeutic strategy that targets both FLT3 and CD99 in FLT3-ITD AML. SIGNIFICANCE: This study investigates a dual-targeting strategy in acute myeloid leukemia (AML), focusing on FLT3 and CD99. The approach demonstrates enhanced therapeutic potential, presenting a novel option for AML treatment.
Asunto(s)
Antígeno 12E7 , Anticuerpos Biespecíficos , Leucemia Mieloide Aguda , Nanopartículas , Tirosina Quinasa 3 Similar a fms , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Animales , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/metabolismo , Humanos , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Ratones , Nanopartículas/química , Antígeno 12E7/metabolismo , Antígeno 12E7/genética , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , FemeninoRESUMEN
FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately one third of acute myeloid leukemia (AML) patients. FLT3-Internal tandem duplication (FLT3-ITD) mutations are the most common FLT3 mutations and are associated with a poor prognosis. Gilteritinib is a FLT3 inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation. While gilteritinib monotherapy has improved patient outcome, few patients achieve durable responses. Combining gilteritinib with venetoclax (VEN) appears to make further improvements, though early results suggest that patients with prior exposure to VEN fair much worse than those without prior exposure. MRX-2843 is a promising inhibitor of FLT3 and MERTK. We recently demonstrated that MRX-2843 is equally potent as gilteritinib in FLT3-ITD AML cell lines in vitro and primary patient samples ex vivo. In this study, we investigated the combination of VEN and MRX-2843 against FLT3-ITD AML cells. We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells. Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases oxidative phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing.