Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma.
Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma.
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DOI：
10.1158/1535-7163.mct-16-0881
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发表时间：
2017-10
影响因子：
5.7
通讯作者：
Raynaud FI
中科院分区：
文献类型：
--
作者：
Ang JE;Pal A;Asad YJ;Henley AT;Valenti M;Box G;de Haven Brandon A;Revell VL;Skene DJ;Venturi M;Rueger R;Meresse V;Eccles SA;de Bono JS;Kaye SB;Workman P;Banerji U;Raynaud FI
MAPK 通路激活经常在人类恶性肿瘤（包括黑色素瘤）中观察到，并且与 MEK 抑制的敏感性和细胞代谢的变化相关。使用基于定量质谱的代谢组学，我们在临床前模型中鉴定了 21 种血浆代谢物，包括氨基酸、丙酰肉碱、磷脂酰胆碱和鞘磷脂，这些代谢物在两个 B-RAF 突变黑色素瘤异种移植物中发生显着改变，并且在单剂量的有效选择性 MEK 抑制剂 RO4987655 后被逆转。对携带 PTEN 缺失 U87MG 人胶质母细胞瘤异种移植物的非肿瘤动物和小鼠进行治疗仅引起血浆中氨基酸和丙酰肉碱的变化。在接受 RO4987655 治疗的晚期黑色素瘤患者中，在疾病进展的患者中观察到治疗中氨基酸的变化，而在应答者中则没有观察到。相反，在反应者中观察到磷脂酰胆碱和鞘磷脂的变化。此外，临床前筛选中确定的 7 种脂质的治疗前水平在统计上能够显着预测对 RO4987655 的客观反应。 RO4987655 治疗相关的变化大于未治疗个体的基线生理变异。这项研究提供了翻译外代谢组血浆读数可预测信号转导抑制剂治疗后的临床疗效以及药效学效用的证据。
MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry-based metabolomics, we identified in preclinical models 21 plasma metabolites including amino acids, propionylcarnitine, phosphatidylcholines and sphingomyelins that were significantly altered in two B-RAF mutant melanoma xenografts and that were reversed following a single dose of the potent and selective MEK inhibitor RO4987655. Treatment of non-tumour bearing animals and mice bearing the PTEN null U87MG human glioblastoma xenograft elicited plasma changes only in amino acids and propionylcarnitine. In patients with advanced melanoma treated with RO4987655, on-treatment changes of amino acids were observed in patients with disease progression and not in responders. In contrast, changes in phosphatidylcholines and sphingomyelins were observed in responders. Furthermore, pre-treatment levels of 7 lipids identified in the preclinical screen were statistically significantly able to predict objective responses to RO4987655. The RO4987655 treatment-related changes were greater than baseline physiological variability in non-treated individuals. This study provides evidence of a translational exo-metabolomic plasma readout predictive of clinical efficacy together with pharmacodynamic utility following treatment with a signal transduction inhibitor.