Euceda Leslie R, Hill Deborah K, Stokke Endre, Hatem Rana, El Botty Rania, Bièche Ivan, Marangoni Elisabetta, Bathen Tone F, Moestue Siver A
Department of Circulation and Medical Imaging, NTNU, The Norwegian University of Science and Technology , Trondheim 7489, Norway.
Department of Radiology, St. Olavs University Hospital , Trondheim 7030, Norway.
J Proteome Res. 2017 May 5;16(5):1868-1879. doi: 10.1021/acs.jproteome.6b00918. Epub 2017 Apr 3.
Patients with triple-negative breast cancer (TNBC) are unresponsive to endocrine and anti-HER2 pharmacotherapy, limiting their therapeutic options to chemotherapy. TNBC is frequently associated with abnormalities in the PI3K/AKT/mTOR signaling pathway; drugs targeting this pathway are currently being evaluated in these patients. However, the response is variable, partly due to heterogeneity within TNBC, conferring a need to identify biomarkers predicting response and resistance to targeted therapy. In this study, we used a metabolomics approach to assess response to the mTOR inhibitor everolimus in a panel of TNBC patient-derived xenografts (PDX) (n = 103 animals). Tumor metabolic profiles were acquired using high-resolution magic angle spinning magnetic resonance spectroscopy. Partial least-squares-discriminant analysis on relative metabolite concentrations discriminated treated xenografts from untreated controls with an accuracy of 67% (p = 0.003). Multilevel linear mixed-effects models (LMM) indicated reduced glycolytic lactate production and glutaminolysis after treatment, consistent with PI3K/AKT/mTOR pathway inhibition. Although inherent metabolic heterogeneity between different PDX models seemed to hinder prediction of treatment response, the metabolic effects following treatment were more pronounced in responding xenografts compared to nonresponders. Additionally, the metabolic information predicted p53 mutation status, which may provide complementary insight into the interplay between PI3K signaling and other drivers of disease progression.
三阴性乳腺癌（TNBC）患者对内分泌治疗和抗HER2药物治疗无反应，这使得他们的治疗选择仅限于化疗。TNBC常与PI3K/AKT/mTOR信号通路异常相关；目前正在对这些患者评估靶向该通路的药物。然而，反应存在差异，部分原因是TNBC内部的异质性，这就需要识别预测靶向治疗反应和耐药性的生物标志物。在本研究中，我们采用代谢组学方法评估了mTOR抑制剂依维莫司对一组TNBC患者来源的异种移植瘤（PDX）（103只动物）的反应。使用高分辨率魔角旋转磁共振波谱获取肿瘤代谢谱。对相对代谢物浓度进行偏最小二乘判别分析，将治疗后的异种移植瘤与未治疗的对照区分开来，准确率为67%（p = 0.003）。多级线性混合效应模型（LMM）表明，治疗后糖酵解乳酸生成和谷氨酰胺分解减少，这与PI3K/AKT/mTOR通路抑制一致。尽管不同PDX模型之间固有的代谢异质性似乎阻碍了对治疗反应的预测，但与无反应的异种移植瘤相比，治疗后有反应的异种移植瘤的代谢效应更为明显。此外，代谢信息预测了p53突变状态，这可能为PI3K信号传导与疾病进展的其他驱动因素之间的相互作用提供补充见解。
