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.

项目总结/摘要 体细胞FMS样酪氨酸激酶3（FLT 3）突变与不良预后相关， 急性髓性白血病（AML）复发率增加。不断有证据表明 FLT 3突变型AML靶向治疗后耐药的遗传依赖性机制 FLT 3抑制剂，包括苯丙氨酸691至亮氨酸（F691 L）突变，已在 接受当前一代FLT 3抑制剂治疗的患者。而含有这种突变的AML细胞 在暴露于FLT 3 i后经历激酶活性和典型FLT 3信号传导的抑制 我们的初步数据显示，FLT 3-F691 L AML细胞继续增殖白血病， 无论是在体外还是在体内。令人困惑的发现是，激酶活性典型的FLT 3信号是 抑制，尽管AML细胞的持续存活，提示激酶非依赖性信号传导 由FLT 3中的F691 L取代产生。本项目的长期目标是了解 FLT 3-F691 L突变的耐药机制，我们认为尚未完全解释 仅通过看门人功能。该项目的具体目标是：（一）确定 FLT 3-ITD和FLT 3-F691 L 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）确定介导的途径和分子 FLT 3-F691 L AML中的激酶非依赖性信号传导，以及（iii）检查FLT 3-F691 L AML的新治疗弱点。 FLT 3-F691 L AML并评估优先的药物联合治疗以克服耐药性。 这项拨款申请的影响是非常重要的，因为它将有翻译的影响，填补 复发性/难治性FLT 3突变AML的未满足需求。如果这种抵抗机制成立， 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， 长期的