Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT Isoforms associated with human malignancies
Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT Isoforms associated with human malignancies
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DOI：
10.1158/0008-5472.can-05-2050
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发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Heinrich, MC
中科院分区：
文献类型：
--
作者：
Schittenhelm, MM;Shiraga, S;Heinrich, MC
KIT激活环的激活突变与某些人类肿瘤相关，包括大多数全身性肥大细胞疾病患者，以及恶性肿瘤、急性髓性白血病（AML）和胃肠道间质瘤（GIST）病例。小分子酪氨酸激酶抑制剂甲磺酸伊马替尼是野生型（WT）KIT和某些突变KIT亚型的有效抑制剂，已成为治疗转移性GIST患者的标准治疗。然而，涉及密码子D816的KIT激活环突变通常见于AML、系统性肥大细胞增多症和半精细胞瘤，对甲磺酸伊马替尼不敏感（IC 50> 5-10 μ mol/L），获得性KIT激活环突变可能与GIST中甲磺酸伊马替尼耐药相关。达沙替尼（原名BMS-354825）是SRC和ABL酪氨酸激酶的小分子ATP竞争性抑制剂，效力在低纳摩尔范围内。一些小分子SRC/ABL抑制剂也具有针对WT KIT激酶的效力。因此，我们假设达沙替尼可能抑制WT和突变型KIT亚型的激酶活性。我们报道。在本文中，达沙替尼有效地抑制WT KIT和胞膜结构域突变KIT自磷酸化和对细胞活力和细胞存活重要下游途径的KIT依赖性活化，所述下游途径例如Ras/促分裂原活化蛋白激酶、磷酸肌醇3-激酶/Akt和Janus活化激酶/信号转导子和转录活化子。此外，达沙替尼是伊马替尼耐药KIT激活环突变体的强效抑制剂，并诱导表达这些突变的肥大细胞抗白血病细胞系的凋亡（对KIT D816 Y>> D81613 > D816 V的效力）。我们的研究表明。达沙替尼可能对人类肿瘤具有临床疗效。与功能获得性KIT突变相关。
Activating mutations of the activation loop of KIT are associated with certain human neoplasms, including the majority of patients with systemic mast cell disorders, as well as cases of seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The small-molecule tyrosine kinase inhibitor imatinib mesylate is a potent inhibitor of wild-type (WT) KIT and certain mutant KIT isoforms and has become the standard of care for treating patients with metastatic GIST. However, KIT activation loop mutations involving codon D816 that are typically found in AML, systemic mastocytosis, and semitioma are insensitive to imatinib mesylate (IC50 > 5-10 mu mol/L), and acquired KIT activation loop mutations can be associated with imatinib mesylate resistance in GIST. Dasatinib (formerly BMS-354825) is a small-molecule, ATP-competitive inhibitor of SRC and ABL tyrosine kinases with potency in the low nanomolar range. Some small-molecule SRC/ABL inhibitors also have potency against WT KIT kinase. Therefore, we hypothesized that dasatinib might inhibit the kinase activity of both WT and mutant KIT isoforms. We report. herein that dasatinib potently inhibits WT KIT and juxtamembrane domain mutant KIT autophosphorylation and KIT-dependent activation of downstream pathways important for cell viability and cell survival, such as Ras/mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and Janus-activated kinase/signal transducers and activators of transcription. Furthermore, dasatinib is a potent inhibitor of imatinib-resistant KIT activation loop mutants and induces apoptosis in mast cell anti leukemic cell lines expressing these mutations (potency against KIT D816Y >> D81613 > D816V). Our studies suggest. that dasatinib may have clinical efficacy against human neoplasms that. tire associated with gain-of-function KIT mutations.