Morotti Alessandro, Mila Silvia, Accornero Paolo, Tagliabue Emma, Ponzetto Carola
Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, C.so Massimo d'Azeglio 52, 10126 Turin, Italy.
Oncogene. 2002 Jul 25;21(32):4885-93. doi: 10.1038/sj.onc.1205622.
The ATP analog K252a is a potent inhibitor for receptor tyrosine kinases of the Trk family. Here we show that nanomolar concentrations of K252a prevent HGF-mediated scattering in MLP-29 cells (30 nM), reduce Met-driven proliferation in GTL-16 gastric carcinoma cells (100 nM), and cause reversion in NIH3T3 fibroblasts transformed by the oncogenic form of the receptor, Tpr-Met (75 nM). K252a inhibits Met autophosphorylation in cultured cells and in immunoprecipitates and prevents activation of its downstream effectors MAPKinase and Akt. Interestingly, K252a seems to be more effective at inhibiting the mutated form of Met (M1268T) found in papillary carcinoma of the kidney than the wild type receptor. Pretreatment of both Tpr-Met-transformed NIH3T3 fibroblasts and of GTL-16 gastric carcinoma cells with K252a results in loss of their ability to form lung metastases in nude mice upon injection into the caudal vein. These observations suggest that K252a derivatives, which are active in vivo as anti-cancer drugs in models of Trk-driven malignancies, should also be effective for treatment of Met-mediated tumors.
ATP类似物K252a是Trk家族受体酪氨酸激酶的有效抑制剂。我们在此表明，纳摩尔浓度的K252a可防止HGF介导的MLP - 29细胞散射（30 nM），降低Met驱动的GTL - 16胃癌细胞增殖（100 nM），并使由受体致癌形式Tpr - Met转化的NIH3T3成纤维细胞发生逆转（75 nM）。K252a抑制培养细胞和免疫沉淀中的Met自磷酸化，并阻止其下游效应器MAP激酶和Akt的激活。有趣的是，K252a在抑制肾乳头状癌中发现的Met突变形式（M1268T）方面似乎比野生型受体更有效。用K252a预处理Tpr - Met转化的NIH3T3成纤维细胞和GTL - 16胃癌细胞，导致它们经尾静脉注射到裸鼠体内后形成肺转移的能力丧失。这些观察结果表明，在Trk驱动的恶性肿瘤模型中作为抗癌药物在体内具有活性的K252a衍生物，也应能有效治疗Met介导的肿瘤。
