通过FDG PET/CT评估的肾细胞癌中葡萄糖蓄积加速表明对酪氨酸激酶抑制剂治疗产生了耐药性。
The acceleration of glucose accumulation in renal cell carcinoma assessed by FDG PET/CT demonstrated acquisition of resistance to tyrosine kinase inhibitor therapy.
作者信息
Nakaigawa Noboru, Kondo Keiichi, Ueno Daiki, Namura Kazuhiro, Makiyama Kazuhide, Kobayashi Kazuki, Shioi Koichi, Ikeda Ichiro, Kishida Takeshi, Kaneta Tomohiro, Minamimoto Ryogo, Tateishi Ukihide, Inoue Tomio, Yao Masahiro
机构信息
Department of Urology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura Kanazawaku, Yokohama, 236-0004, Japan.
Department of Urology, Yokosuka Kyosai Hospital, Yokosuka, Japan.
出版信息
BMC Cancer. 2017 Jan 9;17(1):39. doi: 10.1186/s12885-016-3044-0.
BACKGROUND
Tyrosine-kinase inhibitor (TKI) targeting angiogenesis improves the prognosis of patients with metastatic renal cell carcinoma (RCC), but its effect is temporary. In order to understand the mechanism by which RCC acquires resistance to TKI, we investigated the change of glucose accumulation in RCC by FDG PET/CT when they demonstrated progression disease (PD) against TKI.
METHODS
We monitored the FDG accumulation in RCC of 38 patients treated with TKI by 162 PET/CT sequentially until they were judged to demonstrate PD. Standardized uptake value (SUV), a simplified index of tissue FDG accumulation rate, was measured, and the sequential changes of max SUVmax (the highest SUV in an individual patient) was analyzed. Additionally, the expression of glucose transporter 1 (GLUT-1) and associated proteins in 786-O cells cultured under hypoxia were analyzed.
RESULTS
The 10 patients with RCC which FDG accumulation was accelerated after beginning of TKI treatment demonstrated PD soon. The other 28 patients with RCC which FDG accumulation was suppressed by TKI showed longer progression-free survival (3.6 months vs 6.5 months, P = 0.0026), but this suppression in most cases (96%) was temporary and FDG accumulation was accelerated when tumor demonstrated PD. Interestingly, the FDG accumulation at PD was higher than that before TKI treatment in the half cases. The acceleration of FDG accumulation was suppressed by following treatment by mammalian target of rapamycin (mTOR) inhibitor. Additionally, in vitro assay demonstrated that the expression of GLUT-1 was increased in the RCC cells surviving under hypoxia condition via mTOR pathway.
CONCLUSIONS
The acceleration of glucose accumulation dependent on mTOR in RCC assessed by FDG PET/CT demonstrated acquisition of resistance to TKI. FDG PET/CT had potential as an assessment method monitoring not only the initial response but also following status of RCC during TKI treatment.
TRIAL REGISTRATION
UMIN0000008141 , 11 Jun 2012. This trial was retrospectively registered.
背景
靶向血管生成的酪氨酸激酶抑制剂（TKI）可改善转移性肾细胞癌（RCC）患者的预后，但其效果是暂时的。为了解RCC对TKI产生耐药性的机制，我们通过FDG PET/CT研究了RCC在出现针对TKI的疾病进展（PD）时葡萄糖摄取的变化。
方法
我们通过162次PET/CT连续监测了38例接受TKI治疗的RCC患者的FDG摄取情况，直至判定其出现PD。测量了标准化摄取值（SUV），这是组织FDG摄取率的一个简化指标，并分析了最大SUVmax（个体患者中的最高SUV）的连续变化。此外，还分析了在缺氧条件下培养的786-O细胞中葡萄糖转运蛋白1（GLUT-1）及相关蛋白的表达。
结果
在TKI治疗开始后FDG摄取加速的10例RCC患者很快出现了PD。其他28例FDG摄取被TKI抑制的RCC患者无进展生存期更长（3.6个月对6.5个月，P = 0.0026），但在大多数情况下（96%）这种抑制是暂时的，当肿瘤出现PD时FDG摄取会加速。有趣的是，在一半的病例中，PD时的FDG摄取高于TKI治疗前。后续使用雷帕霉素哺乳动物靶点（mTOR）抑制剂治疗可抑制FDG摄取的加速。此外，体外试验表明，在缺氧条件下存活的RCC细胞中，GLUT-1的表达通过mTOR途径增加。
结论
通过FDG PET/CT评估发现，RCC中依赖mTOR的葡萄糖摄取加速表明其对TKI产生了耐药性。FDG PET/CT不仅有潜力作为一种评估方法监测RCC在TKI治疗期间的初始反应，还能监测后续状态。
试验注册
UMIN0000008141，2012年6月11日。本试验为回顾性注册。
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