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OncoTargets and therapy. 2025 Apr 3:18:489-501. doi: 10.2147/OTT.S479519 Q22.72024

Anti-Tumor Effects of Gilteritinib on FLT3 Mutations: Insights into Resistance Mechanisms in Ba/F3 Cell Models

Gilteritinib靶向FLT3突变的抗肿瘤作用及Ba/F3细胞模型中的耐药机制研究 翻译改进

Taisuke Nakazawa  1, Hirofumi Tsuzuki  1, Tatsuya Kawase  1, Masamichi Mori  1, Taku Yoshida  1

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  • 1 Astellas Pharma Inc, Ibaraki, Japan.
  • DOI: 10.2147/OTT.S479519 PMID: 40196870

    摘要 中英对照阅读

    Background: The efficacy of Fms-like tyrosine kinase 3 (FLT3) inhibitors has been well established against acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) mutations. However, comparative data on the available inhibitors are limited, and drug resistance remains a major concern.

    Methods: This study examined the inhibitory effects of gilteritinib, quizartinib and midostaurin on Ba/F3 cells with FLT3-ITD mutations, or point mutations in the tyrosine kinase domain (TKD-PM) or juxtamembrane domain (JMD-PM), both in vitro and in vivo. Quizartinib and midostaurin were selected as comparators due to their clinical relevance in the AML setting and differing mechanisms of action.

    Results: Gilteritinib showed similar or superior growth inhibition against the majority of FLT3-TKD-PM or FLT3-JMD-PM cells compared to FLT3-ITD-mutant cells. In contrast, the inhibitory effects of quizartinib were reduced on cells with most types of FLT3-TKD-PM, and the inhibitory effects of midostaurin were attenuated on cells with FLT3-TKD-PM N676K. Gilteritinib also effectively suppressed FLT3 autophosphorylation and phosphorylation of signal transducer and activator of transcription 5 (STAT5), AKT and extracellular signal-regulated kinase (ERK) in FLT3-TKD-PM cells, while quizartinib showed a reduced inhibitory effect on FLT3 autophosphorylation and phosphorylation of downstream signaling molecules in FLT3-TKD-PM cells. In mice xenografted with Ba/F3 cells expressing FLT3-ITD mutations or FLT3-TKD-PM, gilteritinib showed a potent antitumor effect, whereas the antitumor effect of quizartinib was significantly diminished in the FLT3-TKD-PM xenograft model.

    Conclusion: These findings highlight the potent efficacy of gilteritinib against a wide range of FLT3 mutations, including TKD-PM and JMD-PM, as well as those associated with resistance to quizartinib or midostaurin. This comparative analysis underscores the need for tailored therapeutic strategies in AML treatment, emphasizing the clinical significance of gilteritinib in overcoming drug resistance.

    Keywords: FLT3-JMD; FLT3-TKD; acute myeloid leukemia; drug resistance; gilteritinib; xenograft mouse models.

    Keywords:gilteritinib; flt3 mutations; resistance mechanisms

    背景: FLT3类似酪氨酸激酶3(FLT3)抑制剂对携带FLT3内部串联重复突变(FLT3-ITD)的急性髓系白血病(AML)的有效性已被充分证实。然而,关于现有抑制剂的比较数据有限,并且药物耐药性仍然是主要问题。

    方法: 本研究在体外和体内考察了吉列替尼、奎扎替尼和米哚妥林对携带FLT3-ITD突变或酪氨酸激酶域(TKD-PM)或近膜区(JMD-PM)点突变的Ba/F3细胞抑制效果。由于这些药物在AML临床应用中的相关性和作用机制的不同,选择奎扎替尼和米哚妥林作为对照。

    结果: 吉列替尼对大多数FLT3-TKD-PM或FLT3-JMD-PM细胞显示出与FLT3-ITD突变细胞相似或更优的生长抑制效果。相比之下,奎扎替尼对携带大多数类型FLT3-TKD-PM细胞的效果减弱,并且米哚妥林在携带FLT3-TKD-PM N676K的细胞中抑制作用降低。吉列替尼还能有效抑制FLT3自磷酸化和信号转导与转录激活因子5(STAT5)、AKT及胞外信号调节激酶(ERK)的磷酸化,而在携带FLT3-TKD-PM细胞中奎扎替尼对FLT3自磷酸化的抑制作用减弱且对其下游信号分子磷酸化的抑制效果也降低。在移植了表达FLT3-ITD突变或FLT3-TKD-PM Ba/F3细胞的小鼠模型中,吉列替尼显示出强大的抗肿瘤效应,而奎扎替尼在FLT3-TKD-PM小鼠模型中的抗肿瘤作用显著减弱。

    结论: 这些发现强调了吉列替尼对包括TKD-PM和JMD-PM在内的各种FLT3突变的强大疗效,以及对抗奎扎替尼或米哚妥林耐药性相关的突变。这种比较分析凸显了AML治疗中定制化治疗策略的需求,并强调了吉列替尼在克服药物耐药性方面的临床意义。

    关键词: FLT3-JMD;FLT3-TKD;急性髓系白血病;药物耐药性;吉列替尼;移植瘤小鼠模型。

    关键词:吉列替尼; FLT3突变; 耐药机制

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    期刊名:Oncotargets and therapy

    缩写:ONCOTARGETS THER

    ISSN:1178-6930

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    IF/分区:2.7/Q2

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    Anti-Tumor Effects of Gilteritinib on FLT3 Mutations: Insights into Resistance Mechanisms in Ba/F3 Cell Models