Schittenhelm Marcus M, Shiraga Sharon, Schroeder Arin, Corbin Amie S, Griffith Diana, Lee Francis Y, Bokemeyer Carsten, Deininger Michael W N, Druker Brian J, Heinrich Michael C
Department of Medicine, Division of Hematology/Oncology, Oregon Health and Science University, Portland, USA.
Cancer Res. 2006 Jan 1;66(1):473-81. doi: 10.1158/0008-5472.CAN-05-2050.
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 seminoma are insensitive to imatinib mesylate (IC50 > 5-10 micromol/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 and leukemic cell lines expressing these mutations (potency against KIT D816Y >> D816F > D816V). Our studies suggest that dasatinib may have clinical efficacy against human neoplasms that are associated with gain-of-function KIT mutations.
KIT激活环的激活突变与某些人类肿瘤相关，包括大多数系统性肥大细胞疾病患者，以及精原细胞瘤、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患者的标准治疗药物。然而，AML、系统性肥大细胞增多症和精原细胞瘤中常见的涉及密码子D816的KIT激活环突变对甲磺酸伊马替尼不敏感（IC50>5-10微摩尔/升），并且获得性KIT激活环突变可能与GIST中的甲磺酸伊马替尼耐药相关。达沙替尼（原BMS-354825）是一种小分子、ATP竞争性的SRC和ABL酪氨酸激酶抑制剂，效力在低纳摩尔范围内。一些小分子SRC/ABL抑制剂对WT KIT激酶也有活性。因此，我们推测达沙替尼可能抑制WT和突变KIT亚型的激酶活性。我们在此报告，达沙替尼有效抑制WT KIT和近膜结构域突变KIT的自磷酸化以及对细胞活力和细胞存活重要的下游途径的KIT依赖性激活，如Ras/丝裂原活化蛋白激酶、磷脂酰肌醇3-激酶/Akt和Janus活化激酶/信号转导子和转录激活子。此外，达沙替尼是伊马替尼耐药的KIT激活环突变体的有效抑制剂，并在表达这些突变的肥大细胞和白血病细胞系中诱导凋亡（对KIT D816Y的效力>>D816F>D816V）。我们的研究表明，达沙替尼可能对与功能获得性KIT突变相关的人类肿瘤具有临床疗效。
