Gene array and fluorescence in situ hybridization biomarkers of activity of saracatinib (AZD0530), a Src inhibitor, in a preclinical model of colorectal cancer.
Gene array and fluorescence in situ hybridization biomarkers of activity of saracatinib (AZD0530), a Src inhibitor, in a preclinical model of colorectal cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-10-0066
复制
发表时间：
2010-08-15
期刊：
影响因子：
--
通讯作者：
Messersmith WA
中科院分区：
文献类型：
--
作者：
Arcaroli JJ;Touban BM;Tan AC;Varella-Garcia M;Powell RW;Eckhardt SG;Elvin P;Gao D;Messersmith WA
评估saracatinib (AZD0530)（一种口服Src抑制剂）在结直肠癌（CRC）中的疗效，并确定预测抗肿瘤活性的生物标志物。23个CRC细胞系暴露于saracatinib，使用基因阵列K-Top Scoring Pairs （K-TSP）方法，使用3个敏感细胞系和8个耐药细胞系的体外和体内基线基因表达谱来预测10个独立的人类CRC外体肿瘤中saracatinib的敏感性。此外，荧光原位杂交法（FISH）和免疫印迹法（immunoblotting）分别检测Src基因拷贝数和Src活化情况。10例外植肿瘤中有2例对saracatinib敏感。K-TSP分类器（TOX>GLIS2、TSPAN7>BCAS4和PARD6G>NXN）在测试集上的准确率达到70%（7 / 10）。FISH对Src基因拷贝数的评估显示Src基因拷贝数的增加和对saracatinib的耐药性有显著性的趋势（P = 0.066）。与耐药肿瘤相比，对saracatinib敏感的肿瘤显示Src和FAK的激活增加。Saracatinib显著降低CRC细胞系和外植体的肿瘤生长。K-TSP分类器（TOX>GLIS2, TSPAN7>BCAS4和PARD6G>NXN）预测对saracatinib的敏感性。此外，Src通路的激活增加与对saracatinib的敏感性相关。这些结果表明FISH （K-TSP分类器）和Src通路的激活在识别可能从saracatinib治疗中获益的CRC患者方面具有潜力。
To evaluate the efficacy of saracatinib (AZD0530), an oral Src inhibitor, in colorectal cancer (CRC) and to identify biomarkers that predict antitumor activity. Twenty-three CRC cell lines were exposed to saracatinib, and baseline gene expression profiles of three sensitive and eight resistant cell lines in vitro and in vivo were used to predict saracatinib sensitivity in an independent group of 10 human CRC explant tumors using the gene array K-Top Scoring Pairs (K-TSP) method. In addition, fluorescence in situ hybridization (FISH) and immunoblotting determined both Src gene copy number and activation of Src, respectively. Two of 10 explant tumors were determined to be sensitive to saracatinib. The K-TSP classifier (TOX>GLIS2, TSPAN7>BCAS4, and PARD6G>NXN) achieved 70% (7 of 10) accuracy on the test set. Evaluation of Src gene copy number by FISH showed a trend toward significance (P = 0.066) with respect to an increase in Src gene copy and resistance to saracatinib. Tumors sensitive to saracatinib showed an increase in the activation of Src and FAK when compared with resistant tumors. Saracatinib significantly decreased tumor growth in a subset of CRC cell lines and explants. A K-TSP classifier (TOX>GLIS2, TSPAN7>BCAS4, and PARD6G>NXN) was predictive for sensitivity to saracatinib. In addition, increased activation of the Src pathway was associated with sensitivity to saracatinib. These results suggest that FISH, a K-TSP classifier, and activation of the Src pathway have potential in identifying CRC patients that would potentially benefit from treatment with saracatinib.