Ma Y, Carter E, Wang X, Shu C, McMahon G, Longley B J
Departments of Dermatology and Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
J Invest Dermatol. 2000 Feb;114(2):392-4. doi: 10.1046/j.1523-1747.2000.00888.x.
Mastocytosis is a neoplastic disease caused at least in part by somatic mutations of the c-KIT proto-oncogene resulting in constitutive activation of its protein product, KIT, the receptor tyrosine kinase for stem cell factor. KIT stimulates mast cell proliferation and prevents apoptosis of neoplastic mast cells. To develop potential therapies for mastocytosis we used indolinones, small molecules that inhibit tyrosine kinases. Four indolinone derivatives (SU4984, SU6663, SU6577, and SU5614) inhibited wild-type KIT, but variably inhibited constitutively activated KIT mutants. SU4984, SU6577, and SU5614 were effective against KIT with juxtamembrane activating mutations, whereas only SU6577 could suppress KIT containing either juxtamembrane or kinase domain activating mutations. Furthermore, SU4984, SU6577, and SU5614 killed neoplastic mast cells expressing a juxtamembrane-mutated KIT, whereas SU4984 and SU6577 killed neoplastic mast cells expressing KIT bearing a kinase domain mutation. These data show a direct correlation between inhibition of constitutively activated KIT and the death of neoplastic mast cells, and point to specific tyrosine kinase inhibitors as a potential therapy aimed directly at a cause of mastocytosis.
肥大细胞增多症是一种肿瘤性疾病，至少部分由c-KIT原癌基因的体细胞突变引起，导致其蛋白产物KIT（干细胞因子的受体酪氨酸激酶）的组成性激活。KIT刺激肥大细胞增殖并防止肿瘤性肥大细胞凋亡。为了开发针对肥大细胞增多症的潜在疗法，我们使用了吲哚酮类化合物，即抑制酪氨酸激酶的小分子。四种吲哚酮衍生物（SU4984、SU6663、SU6577和SU5614）抑制野生型KIT，但对组成性激活的KIT突变体的抑制作用各不相同。SU4984、SU6577和SU5614对具有近膜激活突变的KIT有效，而只有SU6577能够抑制含有近膜或激酶结构域激活突变的KIT。此外，SU4984、SU6577和SU5614杀死表达近膜突变KIT的肿瘤性肥大细胞，而SU4984和SU6577杀死表达激酶结构域突变KIT的肿瘤性肥大细胞。这些数据表明组成性激活的KIT的抑制与肿瘤性肥大细胞的死亡之间存在直接相关性，并指出特定的酪氨酸激酶抑制剂作为一种直接针对肥大细胞增多症病因的潜在疗法。
