Momelotinib is a highly potent inhibitor of FLT3-mutant AML.
Momelotinib is a highly potent inhibitor of FLT3-mutant AML.
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DOI：
10.1182/bloodadvances.2021004611
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发表时间：
2022-02-22
期刊：
影响因子：
7.5
通讯作者：
Azam M
中科院分区：
文献类型：
--
作者：
Azhar M;Kincaid Z;Kesarwani M;Ahmed A;Wunderlich M;Latif T;Starczynowski D;Azam M
Momelotinib 对 FLT3 突变的 AML 细胞（包括 quizartinib 耐药的激活环变体）表现出高效。 Momelotinib 可有效抑制 FLT3 配体和造血细胞因子（GM-CSF 和 IL-3）带来的内在耐药性。尽管引入了更具选择性的 FLT3 抑制剂来治疗 FLT3 突变的急性髓系白血病 (AML)，但缓解期很短，并且患者在初次缓解后表现出疾病进展。获得耐药性基因突变和生长因子信号传导是导致复发的两个主要机制。针对这两种逃逸机制的 FLT3 抑制剂可能会产生更深刻、更持久的临床反应。在这里，我们证明 JAK2 抑制剂 momelotinib 是一种等效的 1 型 FLT3 抑制剂。 Momelotinib 在小鼠和人类原代细胞中显示出对 FLT3 内部串联重复的有效抑制，并有效抑制残基 D835、D839 和 Y842 激活环内的临床相关耐药变体。此外，莫莫替尼还能有效抑制生长因子和造血细胞因子激活的 JAK2 信号传导介导的耐药性。因此，在 AML 临床前小鼠模型中，通过同时抑制 FLT3 和生长因子信号传导，莫莫替尼治疗显示出更好的抑制白血病的功效。总而言之，这些数据提供的证据表明，莫莫替尼是一种有效的 1 型双 JAK2/FLT3 抑制剂，并可能提供吉特替尼的替代品。它能够阻碍生长因子信号传导和激活环突变体产生的耐药性，这表明莫莫替尼治疗可以提供更深入和持久的反应，因此值得进行临床评估。
Momelotinib shows high efficacy against FLT3-mutated AML cells, including quizartinib-resistant activation loop variants. Momelotinib effectively suppresses intrinsic resistance conferred by FLT3 ligand and hematopoietic cytokines (GM-CSF and IL-3). Despite the introduction of more selective FLT3 inhibitors to treat FLT3-mutated acute myeloid leukemia (AML), remissions are short lived, and patients show progressive disease after an initial response. Acquisition of resistance-conferring genetic mutations and growth factor signaling are 2 principal mechanisms that drive relapse. FLT3 inhibitors targeting both escape mechanisms could lead to a more profound and lasting clinical response. Here, we show that the JAK2 inhibitor momelotinib is an equipotent type 1 FLT3 inhibitor. Momelotinib showed potent inhibition of FLT3-internal tandem duplication in mouse and human primary cells and effectively suppressed its clinically relevant resistant variants within the activation loop at residues D835, D839, and Y842. Additionally, momelotinib efficiently suppressed the resistance mediated by growth factors and hematopoietic cytokine-activated JAK2 signaling. Consequently, concomitant inhibition of FLT3 and suppression of growth factor signaling by momelotinib treatment showed better efficacy in suppressing leukemia in a preclinical murine model of AML. Altogether, these data provide evidence that momelotinib is an effective type 1 dual JAK2/FLT3 inhibitor and may offer an alternative to gilteritinib. Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response and, thus, warrants its clinical evaluation.