In vivo Antitumor Activity of MEK and Phosphatidylinositol 3-Kinase Inhibitors in Basal-Like Breast Cancer Models
In vivo Antitumor Activity of MEK and Phosphatidylinositol 3-Kinase Inhibitors in Basal-Like Breast Cancer Models
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DOI：
10.1158/1078-0432.ccr-09-0317
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发表时间：
2009-07-15
影响因子：
11.5
通讯作者：
Lackner, Mark R.
中科院分区：
文献类型：
--
作者：
Hoeflich, Klaus P.;O'Brien, Carol;Lackner, Mark R.
目的：基底细胞样乳腺癌的潜在途径知之甚少，到目前为止，还没有批准的针对这种疾病的靶向治疗。我们研究了丝裂原活化蛋白激酶激酶（MEK）和磷脂酰肌醇3-激酶（PI 3 K）抑制剂作为基底样乳腺癌靶向治疗的作用。我们使用药物基因组学分析的一个大面板乳腺癌细胞系与详细的伴随分子信息，以确定分子预测的反应，有效的和选择性的MEK抑制剂，并确定分子机制，联合MEK和PI 3 K靶向治疗基底细胞样乳腺癌。通过在多个肿瘤异种移植物models.Results中的测试，我们发现基底样乳腺癌模型具有激活的RAS样转录程序，并且与代表其他乳腺癌亚型的模型相比，对MEK的选择性抑制剂表现出更大的敏感性。我们还发现，PTEN的缺失是对MEK抑制反应的负向预测因子，选择性MEK抑制剂治疗导致PI 3 K通路信号传导上调，PI 3 K和MEK/细胞外信号调节激酶信号传导的双重阻断协同作用，在体外和体内有效地损害基底样乳腺癌模型的生长。我们的研究表明，单药MEK抑制剂是一种有前途的治疗方式与完整的PTEN基底样乳腺癌，也提供了一个合理的组合MEK和PI 3 K抑制剂在基底样癌与完整和缺失的PTEN的基础。
Purpose: The pathways underlying basal-like breast cancer are poorly understood, and as yet, there is no approved targeted therapy for this disease. We investigated the role of mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitors as targeted therapies for basal-like breast cancer.Experimental Design: We used pharmacogenomic analysis of a large panel of breast cancer cell lines with detailed accompanying molecular information to identify molecular predictors of response to a potent and selective inhibitor of MEK and also to define molecular mechanisms underlying combined MEK and PI3K targeting in basal-like breast cancer. Hypotheses were confirmed by testing in multiple tumor xenograft models.Results: We found that basal-like breast cancer models have an activated RAS-like transcriptional program and show greater sensitivity to a selective inhibitor of MEK compared with models representative of other breast cancer subtypes. We also showed that loss of PTEN is a negative predictor of response to MEK inhibition, that treatment with a selective MEK inhibitor caused up-regulation of PI3K pathway signaling, and that dual blockade of both PI3K and MEK/extracellular signal-regulated kinase signaling synergized to potently impair the growth of basal-like breast cancer models in vitro and in vivo.Conclusions: Our studies suggest that single-agent MEK inhibition is a promising therapeutic modality for basal-like breast cancers with intact PTEN, and also provide a basis for rational combination of MEK and PI3K inhibitors in basal-like cancers with both intact and deleted PTEN.