Preclinical In vivo Evaluation of Efficacy, Pharmacokinetics, and Pharmacodynamics of a Novel MEK1/2 Kinase Inhibitor RO5068760 in Multiple Tumor Models
Preclinical In vivo Evaluation of Efficacy, Pharmacokinetics, and Pharmacodynamics of a Novel MEK1/2 Kinase Inhibitor RO5068760 in Multiple Tumor Models
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DOI：
10.1158/1535-7163.mct-09-0601
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发表时间：
2010-01-01
影响因子：
5.7
通讯作者：
Niu, Huifeng
中科院分区：
文献类型：
--
作者：
Daouti, Sherif;Higgins, Brian;Niu, Huifeng
针对Ras/Raf/丝裂原活化蛋白激酶激酶（MEK）/细胞外信号调节激酶（ERK）通路是一种有前景的抗癌策略。最近，我们报道了一类新型的强效且选择性的非ATP竞争性MEK1/2抑制剂，其具有独特的结构和作用机制。RO5068760是这类抑制剂的代表，在多种有丝裂原活化蛋白激酶通路异常激活的肿瘤中显示出显著疗效。为了了解全身暴露量与靶点（MEK1/2）抑制以及肿瘤生长抑制之间的关系，本研究详细描述了RO5068760在多种异种移植肿瘤模型中的体内药效、药代动力学和药效动力学特征。通过磷酸化ERK水平来衡量MEK1/2的抑制情况，在LOX黑色素瘤和HT - 29结直肠癌模型中，血浆中估计的半数有效浓度（EC₅₀）分别为1.36 μmol/L（880 ng/mL）和3.35 μmol/L（2168 ng/mL）。在猴子外周血淋巴细胞中观察到类似的EC₅₀（1.41 μmol/L或915 ng/mL）。为了实现肿瘤生长抑制（≥90%），在B - RafV600E或K - Ras突变肿瘤模型中，分别需要平均血浆药物浓度为0.65或5.23 μmol/L，这与体外测定的细胞生长抑制的90%抑制浓度（IC₉₀）值（0.64或4.1 μmol/L）非常相似。在体内全身暴露量相同的情况下，RO5068760在携带B - RafV600E突变的肿瘤中显示出更优的疗效。血浆浓度 - 时间曲线表明，持续的磷酸化ERK抑制（>50%）可能不是达到最佳疗效所必需的，尤其是在高反应性肿瘤中。这项研究可能有助于未来临床试验设计，利用生化标志物进行早期机制验证以及选择合适的患者和最佳给药方案。《分子癌症治疗》；9(1)；134 - 144。（C）2010美国癌症研究协会。
Targeting the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway represents a promising anticancer strategy. Recently, we have reported a novel class of potent and selective non-ATP-competitive MEK1/2 inhibitors with a unique structure and mechanism of action. RO5068760 is a representative of this class showing significant efficacy in a broad spectrum of tumors with aberrant mitogen-activated protein kinase pathway activation. To understand the relationship between systemic exposures and target (MEK1/2) inhibition as well as tumor growth inhibition, the current study presents a detailed in vivo characterization of efficacy, pharmacokinetics, and pharmacodynamics of RO5068760 in multiple xenograft tumor models. For inhibition of MEK1/2 as measured by the phosphorylated ERK levels, the estimated EC(50)s in plasma were 1.36 mu mol/L (880 ng/mL) and 3.35 mu mol/L (2168 ng/mL) in LOX melanoma and HT-29 colorectal cancer models, respectively. A similar EC50 (1.41 mu mol/L or 915 ng/mL) was observed in monkey peripheral blood lymphocytes. To achieve tumor growth inhibition (>= 90%), an average plasma drug concentration of 0.65 or 5.23 mu mol/L was required in B-RafV600E or K-Ras mutant tumor models, respectively, which were remarkably similar to the IC90 values (0.64 or 4.1 mu mol/L) determined in vitro for cellular growth inhibition. With equivalent in vivo systemic exposures, RO5068760 showed superior efficacy in tumors harboring B-RafV600E mutation. The plasma concentration time profiles indicate that constant p-ERK suppression (>50%) may not be required for optimal efficacy, especially in highly responsive tumors. This study may facilitate future clinical trial design in using biochemical markers for early proof of mechanism and in selecting the right patients and optimal dose regimen. Mol Cancer Ther; 9(1); 134-44. (C) 2010 AACR.