Dabrafenib therapy for metastatic melanoma focuses on blocking growth-promoting signals produced by a hyperactive BRAF protein. We report the metabolic differences of four human melanoma cell lines with diverse responses to dabrafenib therapy (30 mg/kg; oral): WM3918 < WM9838BR < WM983B < DB-1. Our goal was to determine if metabolic changes produced by the altered signaling pathway due toBRAFmutations differ in the melanoma models and whether these differences correlate with response to treatment. We assessed metabolic changes in isolated cells using high-resolution proton magnetic resonance spectroscopy (1H MRS) and supplementary biochemical assays. We also noninvasively studied mouse xenografts using proton and phosphorus (1H/31P) MRS. We found consistent changes in lactate and alanine, either in isolated cells or mouse xenografts, correlating with their relative dabrafenib responsiveness. In xenografts, we also observed that a more significant response to dabrafenib correlated with higher bioenergetics (i.e., increased βNTP/Pi). Notably, our noninvasive assessment of the metabolic status of the human melanoma xenografts by1H/31P MRS demonstrated early metabolite changes preceding therapy response (i.e., tumor shrinkage). Therefore, this noninvasive methodology could be translated to assess in vivo predictive metabolic biomarkers of response in melanoma patients under dabrafenib and probably other signaling inhibition therapies.
达拉非尼治疗转移性黑色素瘤主要通过抑制过度活跃的BRAF蛋白产生的促生长信号。本研究报道了四种对达拉非尼治疗（30 mg/kg；口服）反应各异的人黑色素瘤细胞系（WM3918 < WM9838BR < WM983B < DB-1）的代谢差异。研究旨在探究由BRAF突变引起信号通路改变所导致的代谢变化在不同黑色素瘤模型中是否存在差异，以及这些差异是否与治疗反应相关。我们采用高分辨率质子磁共振波谱（1H MRS）及补充生化检测方法评估了离体细胞的代谢变化，并利用质子与磷（1H/31P）MRS对小鼠移植瘤模型进行了无创研究。研究发现，无论是在离体细胞还是小鼠移植瘤中，乳酸和丙氨酸的变化均与其对达拉非尼的相对反应性相关。在移植瘤模型中，我们还观察到更强的达拉非尼治疗反应与更高的生物能量状态（即βNTP/Pi比值升高）相关。值得注意的是，通过1H/31P MRS对黑色素瘤移植瘤代谢状态的无创评估显示，在治疗反应（即肿瘤缩小）出现前已存在早期代谢物变化。因此，这种无创检测方法有望转化为临床评估工具，用于监测黑色素瘤患者接受达拉非尼及其他信号通路抑制剂治疗时的体内预测性代谢生物标志物。
Metabolic Imaging Biomarkers of Response to Signaling Inhibition Therapy in Melanoma
肿瘤(癌症)患者之家