Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies.
Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies.
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DOI：
10.1158/1535-7163.mct-10-1044
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发表时间：
2011-06
影响因子：
5.7
通讯作者：
Rivera VM
中科院分区：
文献类型：
--
作者：
Gozgit JM;Wong MJ;Wardwell S;Tyner JW;Loriaux MM;Mohemmad QK;Narasimhan NI;Shakespeare WC;Wang F;Druker BJ;Clackson T;Rivera VM
Ponatinib（AP 24534）是一种新型多靶点激酶抑制剂，可在临床可达到的药物水平下有效抑制天然和突变型BCR-ABL。泊那替尼还对其他血液恶性肿瘤发病机制中涉及的一组离散激酶具有体外抑制活性，包括FLT 3、KIT、成纤维细胞生长因子受体1（FGFR 1）和血小板衍生生长因子受体α（PDGFRα）。在这里，使用含有这些受体的活化形式的白血病细胞系，我们表明泊那替尼有效抑制受体磷酸化和细胞增殖，其IC 50值与抑制BCR-ABL所需的IC 50值相当（0.3至20 nmol/L）。泊那替尼对FLT 3-ITD突变体的活性尤其显著，该突变体见于高达30%的急性髓性白血病（AML）患者。在MV 4 -11（FLT 3-ITD+/+）而非RS 4;11（FLT 3-ITD−/−）AML细胞中，泊那替尼在低于10 nmol/L的浓度下抑制FLT 3信号传导并诱导细胞凋亡。在MV 4 -11小鼠异种移植模型中，泊那替尼每日一次经口给药导致信号传导和肿瘤消退的剂量依赖性抑制。泊那替尼抑制来自FLT 3-ITD阳性AML患者的原发性白血病原始细胞的活力（IC 50 4 nmol/L），但不抑制从3例表达天然FLT 3的AML患者中分离的原始白血病原始细胞的活力。总体而言，这些结果支持在FLT 3-ITD驱动的AML和KIT、FGFR 1或PDGFRα驱动的其他血液学恶性肿瘤患者中研究泊那替尼。
Ponatinib (AP24534) is a novel multitargeted kinase inhibitor that potently inhibits native and mutant BCR-ABL at clinically achievable drug levels. Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including FLT3, KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor α (PDGFRα). Here, using leukemic cell lines containing activated forms of each of these receptors, we show that ponatinib potently inhibits receptor phosphorylation and cellular proliferation with IC50 values comparable to those required for inhibition of BCR-ABL (0.3 to 20 nmol/L). The activity of ponatinib against the FLT3-ITD mutant, found in up to 30% of acute myeloid leukemia (AML) patients, was particularly notable. In MV4-11 (FLT3-ITD+/+) but not RS4;11 (FLT3-ITD−/−) AML cells, ponatinib inhibited FLT3 signaling and induced apoptosis at concentrations of less than 10 nmol/L. In an MV4-11 mouse xenograft model, once daily oral dosing of ponatinib led to a dose-dependent inhibition of signaling and tumor regression. Ponatinib inhibited viability of primary leukemic blasts from a FLT3-ITD positive AML patient (IC50 4 nmol/L) but not those isolated from 3 patients with AML expressing native FLT3. Overall, these results support the investigation of ponatinib in patients with FLT3-ITD–driven AML and other hematologic malignancies driven by KIT, FGFR1, or PDGFRα.