Intermittent Administration of MEK Inhibitor GDC-0973 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth Inhibition
Intermittent Administration of MEK Inhibitor GDC-0973 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth Inhibition
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DOI：
10.1158/0008-5472.can-11-1515
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发表时间：
2012-01-01
期刊：
影响因子：
11.2
通讯作者：
Belvin, Marcia
中科院分区：
文献类型：
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作者：
Hoeflich, Klaus P.;Merchant, Mark;Belvin, Marcia
MAP/ERK激酶（MEK）和磷酸肌苷3激酶（PI3K）抑制剂的组合在临床前癌症模型中显示出前景，导致联合靶向这两个关键癌症信号通路的临床试验开始。GDC-0973是一种新型的选择性mekin抑制剂，GDC-0941是一种I类PI3K抑制剂，目前正处于单药和联合用药的早期临床试验阶段。这些选择性抑制剂的发现使得研究RAS下游两个主要信号分支抑制剂联合的精确效果成为可能。在这里，我们研究了丝裂原活化蛋白激酶（MAPK）和PI3K途径中的多个生物标志物，以寻找解释细胞凋亡增加的趋同点。通过体外洗脱研究和小鼠交替给药方案，我们发现间歇性抑制PI3K和MAPK通路足以对BRAF和KRAS突变癌细胞有效。GDC-0973与PI3K抑制剂GDC-0941联合使用，通过诱导与凋亡相关的生物标志物，包括Bcl-2家族促凋亡调节因子，在体外和体内产生联合疗效。因此，这些数据表明，在临床前癌症模型中，MEK和PI3K抑制剂联合使用并不需要持续暴露，并且可以观察到间歇性给药对下游细胞凋亡生物标志物的持续影响。癌症Res;72 (1);210 - 9。(c) 2011年aacr。
Combinations of MAP/ERK kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors have shown promise in preclinical cancer models, leading to the initiation of clinical trials cotargeting these two key cancer signaling pathways. GDC-0973, a novel selective MEKinhibitor, and GDC-0941, a class I PI3K inhibitor, are in early stage clinical trials as both single agents and in combination. The discovery of these selective inhibitors has allowed investigation into the precise effects of combining inhibitors of two major signaling branches downstream of RAS. Here, we investigated multiple biomarkers in the mitogen-activated protein kinase (MAPK) and PI3K pathway to search for points of convergence that explain the increased apoptosis seen in combination. Using washout studies in vitro and alternate dosing schedules in mice, we showed that intermittent inhibition of the PI3K and MAPK pathway is sufficient for efficacy in BRAF and KRAS mutant cancer cells. The combination of GDC-0973 with the PI3K inhibitor GDC-0941 resulted in combination efficacy in vitro and in vivo via induction of biomarkers associated with apoptosis, including Bcl-2 family proapoptotic regulators. Therefore, these data suggest that continuous exposure of MEK and PI3K inhibitors in combination is not required for efficacy in preclinical cancer models and that sustained effects on downstream apoptosis biomarkers can be observed in response to intermittent dosing. Cancer Res; 72(1); 210-9. (C) 2011 AACR.