Kinase-independent mechanism of resistance to FLT3 inhibitors in AML

项目摘要/摘要 体细胞FMS样酪氨酸激酶3(Flt3)突变与不良预后和 急性髓系白血病(AML)的复发率增加。有不断变化的证据描述 靶向治疗后Flt3基因突变AML耐药的遗传机制 Flt3抑制剂，包括苯丙氨酸691到亮氨酸(F691L)的突变，已在 接受新一代Flt3抑制剂治疗的患者。而含有这种突变的AML细胞 暴露于Flt3i后对激酶活性和典型的Flt3信号的抑制 治疗后，我们的初步数据显示，Flt3-F691L AML细胞继续增殖白血病 在体外和体内都有。令人困惑的是，发现激酶活性是典型的Flt3信号 尽管AML细胞仍在存活，但仍受到抑制，这表明信号转导不依赖于激酶 这是由Flt3中的F691L替换引起的。该项目的长期目标是了解 Flt3-F691L突变的耐药机制，我们认为尚未完全解释 仅通过网守功能。该项目的具体目标是：(一)确定 Flt3-ITD和Flt3-F691L AML细胞中依赖和非依赖的信号转导 分化、生存和基因表达，(Ii)确定介导 Flt3-F691L AML中的激酶非依赖性信号转导，以及(Iii)检查新的治疗易感性 Flt3-F691L急性髓系白血病，并评估克服耐药性的优先药物联合疗法。 这项拨款申请的影响是非常显著的，因为它将产生翻译方面的影响， 对复发/难治性Flt3突变AML的未满足需求。如果这种抵抗机制成立， 这可能为各种儿科癌症类型的药物开发和联合治疗提供信息。 长期的。

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.