Kinase-independent mechanism of resistance to FLT3 inhibitors in AML

AML 中 FLT3 抑制剂的非激酶依赖性耐药机制

• 批准号: 10661971
• 负责人: LaQuita M Jones
• 金额: $ 26.22万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661971
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adaptor Signaling Protein; Affect; Affinity; Applications Grants; Binding; Binding Sites; Biological; Biology; CRISPR screen; Cell Line; Cell Proliferation; Cell Survival; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Codon Nucleotides; Combined Modality Therapy; Data; Dependence; Development; Engineering; Exhibits; Exposure to; FLT3 gene; Gatekeeping; Gene Expression; Generations; Genes; Genetic; Goals; Human; In Vitro; Leucine; Leukemic Cell; Libraries; MAP Kinase Gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Modeling; Molecular Abnormality; Molecular Target; Mutate; Mutation; Oncogenic; Outcome; PI3K/AKT; Pathway interactions; Patients; Pediatrics; Phenylalanine; Phosphotransferases; Point Mutation; Prognosis; Recurrent disease; Refractory; Refractory Disease; Relapse; Reporting; Research; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Specificity; Stat5 protein; Testing; Therapeutic; Time; Toxic effect; acute myeloid leukemia cell; cancer type; chemotherapy; combinatorial; drug development; experience; high risk population; improved; in vivo; inhibitor; inhibitor therapy; knock-down; leukemia; mutant; new therapeutic target; next generation; novel; novel therapeutics; pharmacologic; recruit; resistance mechanism; targeted treatment; therapeutic candidate; therapeutic target; tool; whole genome

Project Summary/Abstract Somatic FMS-like tyrosine kinase 3 (FLT3) mutations are associated with a poor prognosis and increased rates of relapse in acute myeloid leukemia (AML). There is evolving evidence describing genetic-dependent mechanisms of resistance in FLT3-mutant AML following targeted therapy with FLT3 inhibitors, including the phenylalanine 691 to leucine (F691L) mutation that has been reported in patients treated with current generation of FLT3 inhibitors. While AML cells containing this mutation experience inhibition of kinase activity and canonical FLT3 signaling following exposure to FLT3i treatment, our preliminary data revealed that FLT3-F691L AML cells continued propagating leukemia both in vitro and in vivo. The perplexing finding that kinase activity canonical FLT3 signaling is suppressed, despite ongoing survival of the AML cells, suggested kinase independent signaling resulting from F691L substitution in FLT3. The long-term goal of this project is understanding the mechanism of resistance underlying the FLT3-F691L mutation, which we believe is not fully explained by gatekeeper functionality solely. The specific aims for this project are: (i) determine the effects of kinase-dependent and -independent signaling in FLT3-ITD and FLT3- F691L AML cells on differentiation, survival, and gene expression, (ii) identify the pathways and molecules mediating kinase-independent signaling in FLT3-F691L AML, and (iii) examine novel therapeutic vulnerabilities for FLT3-F691L AML and evaluate prioritized pharmacologic combination therapy to overcome resistance. The impact of this grant application is highly significant, as it will have translational implications, filling an unmet need for relapsed/refractory FLT3 mutant AML. If this mechanism of resistance holds true, this could inform drug development and combinatorial therapies for various pediatric cancer types in the long-term.

项目摘要/摘要 体细胞FMS样酪氨酸激酶3（FLT3）突变与预后不良有关 急性髓样白血病（AML）的复发率增加。有描述的证据不断发展 靶向治疗后，FLT3突变剂AML的遗传依赖性机制与 FLT3抑制剂，包括苯丙氨酸691至亮氨酸（F691L）突变 接受当前GLT3抑制剂治疗的患者。而含有这种突变的AML细胞 暴露于FLT3I后，经验抑制激酶活性和规范FLT3信号传导 治疗，我们的初步数据表明，FLT3-F691L AML细胞继续传播白血病 体外和体内。令人困惑的发现激酶活性规范FLT3信号是 尽管AML细胞持续存活，但建议激酶独立信号传导 由FLT3中的F691L取代。该项目的长期目标是了解 FLT3-F691L突变的抗药性机制，我们认为这不是完全解释的 仅通过网守功能。该项目的具体目的是：（i）确定 FLT3-ITD和FLT3-F691L AML细胞中的激酶依赖性和非依赖性信号传导 分化，生存和基因表达，（ii）识别介导的途径和分子 FLT3-F691L AML中的激酶非依赖性信号传导，（iii）检查新的治疗脆弱性 FLT3-F691L AML并评估优先的药理联合疗法以克服耐药性。 该赠款申请的影响非常重要，因为它将具有翻译含义，填充 对复发/难治性FLT3突变体AML的未满足。如果这种抵抗机制是正确的， 这可以为各种儿科癌症类型的药物开发和组合疗法提供信息 长期。