Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244).
Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244).
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DOI：
10.1158/0008-5472.can-09-1577
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发表时间：
2010-03-15
期刊：
影响因子：
11.2
通讯作者：
Smith PD
中科院分区：
文献类型：
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作者：
Dry JR;Pavey S;Pratilas CA;Harbron C;Runswick S;Hodgson D;Chresta C;McCormack R;Byrne N;Cockerill M;Graham A;Beran G;Cassidy A;Haggerty C;Brown H;Ellison G;Dering J;Taylor BS;Stark M;Bonazzi V;Ravishankar S;Packer L;Xing F;Solit DB;Finn RS;Rosen N;Hayward NK;French T;Smith PD
Selumetinib （AZD6244, array -142886）是一种选择性的、非atp竞争性的丝裂原活化蛋白/细胞外信号调节激酶(MEK)-1/2抑制剂。临床前和患者的抗肿瘤活性范围突出了确定对该药物反应的决定因素的重要性。在不同谱系的大型肿瘤细胞组中，我们发现MEK抑制剂反应与突变或BRAF/MEK、RAS或磷酸肌肽3激酶（PI3K）活性的磷酸化蛋白标志物没有绝对相关性。我们的目标是通过共调节基因网络测量途径输出来提高预测能力，这些基因网络显示抗性细胞亚群独有的差异mRNA表达，并与突变或动态途径活性相关。我们发现了一个18个基因标记，可以独立于肿瘤基因型测量MEK功能输出。当MEK通路被激活，但细胞仍然对selumetinib具有抗性时，我们发现了一个13个基因的标记，暗示存在来自RAS效应器的代偿信号，而不是PI3K。这些特征根据MEK的功能激活和/或selumetinib敏感性对样品进行分层的能力在多个独立的黑色素瘤、结肠癌、乳腺癌和肺癌细胞系以及异种移植模型中得到了证明。此外，我们能够使用单一的基于rt - qpcr的测试在固定档案黑色素瘤样本中测量这些特征，并发现基因间相关性和与途径活性遗传标记的关联被保存下来。这些特征为MEK生物学研究和MEK抑制剂的临床应用提供了有用的工具，并且所采取的新方法可能有益于其他靶向治疗。
Selumetinib (AZD6244, ARRY-142886) is a selective, non–ATP-competitive inhibitor of mitogen-activated protein/extracellular signal–regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR–based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.