Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Advanced Imaging Research, Inc., Cleveland, OH 44114, USA.
Cells. 2024 Jul 19;13(14):1220. doi: 10.3390/cells13141220.
The MAPK signaling pathway with mutations has been shown to drive the pathogenesis of 40-60% of melanomas. Inhibitors of this pathway's BRAF and MEK components are currently used to treat these malignancies. However, responses to these treatments are not always successful. Therefore, identifying noninvasive biomarkers to predict treatment responses is essential for personalized medicine in melanoma. Using noninvasive H magnetic resonance spectroscopy (H MRS), we previously showed that BRAF inhibition reduces lactate and alanine tumor levels in the early stages of effective therapy and could be considered as metabolic imaging biomarkers for drug response. The present work demonstrates that these metabolic changes observed by H MRS and those assessed by P MRS are also found in preclinical human melanoma models treated with MEK inhibitors. Apart from H and P MRS, additional supporting in vitro biochemical analyses are described. Our results indicate significant early metabolic correlations with response levels to MEK inhibition in the melanoma models and are consistent with our previous study of BRAF inhibition. Given these results, our study supports the potential clinical utility of noninvasive MRS to objectively image metabolic biomarkers for the early prediction of melanoma's response to MEK inhibition.
MAPK 信号通路的突变已被证明驱动了 40-60%的黑色素瘤的发病机制。目前，该通路的 BRAF 和 MEK 成分抑制剂被用于治疗这些恶性肿瘤。然而，这些治疗的反应并不总是成功的。因此，确定非侵入性的生物标志物来预测治疗反应对于黑色素瘤的个性化医学至关重要。使用非侵入性 H 磁共振波谱（H MRS），我们之前表明 BRAF 抑制在有效治疗的早期阶段降低了乳酸盐和丙氨酸肿瘤水平，并且可以被认为是药物反应的代谢成像生物标志物。本工作表明，在接受 MEK 抑制剂治疗的临床前人类黑色素瘤模型中，也观察到了 H MRS 观察到的这些代谢变化和 P MRS 评估的代谢变化。除了 H 和 P MRS 外，还描述了其他支持的体外生化分析。我们的结果表明，在黑色素瘤模型中，与 MEK 抑制反应水平的早期代谢相关性显著，这与我们之前对 BRAF 抑制的研究一致。鉴于这些结果，我们的研究支持使用非侵入性 MRS 来客观成像代谢生物标志物，以早期预测黑色素瘤对 MEK 抑制的反应的潜在临床应用。
