Okabe Ko, Tanaka Toshiaki, Shindo Tetsuya, Kyoda Yuki, Nishida Sachiyo, Hashimoto Kohei, Kobayashi Ko, Masumori Naoya
Department of Urology, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan.
Curr Oncol. 2025 Jul 8;32(7):391. doi: 10.3390/curroncol32070391.
This study aimed to clarify the alterations in gene expression in metastatic renal cell carcinoma (mRCC) during disease progression and in response to treatment with immune checkpoint inhibitors using a syngeneic mouse mRCC model. RENCA cells were orthotopically implanted in BALB/c mice. Mice received first-line treatment with cabozantinib, anti-PD-1 antibody, or a combination. Tumor progression was monitored using serial micro-computed tomography. Lung metastasis samples were collected, and RNA sequencing was performed. Mice with apparent disease progression received second-line treatment with axitinib, everolimus, or lenvatinib after combination therapy. The median overall survival was 28, 34, 34, and 49 days in untreated mice and those treated with cabozantinib, anti-PD-1, or their combination, respectively ( < 0.05). RNA sequencing revealed upregulation of the fibroblast growth factor pathway in lung metastases after monotherapy, whereas mTOR pathway activation was observed only after combination therapy. Treatment-specific gene expression changes occur in mRCC, suggesting that the optimal target for sequential therapy in mRCC varies depending on prior treatment.
本研究旨在利用同基因小鼠肾细胞癌模型，阐明转移性肾细胞癌（mRCC）在疾病进展过程中以及对免疫检查点抑制剂治疗反应时的基因表达变化。将RENCA细胞原位植入BALB/c小鼠体内。小鼠接受卡博替尼、抗PD-1抗体或联合用药的一线治疗。使用连续微型计算机断层扫描监测肿瘤进展。收集肺转移样本并进行RNA测序。联合治疗后疾病明显进展的小鼠接受阿昔替尼、依维莫司或乐伐替尼的二线治疗。未治疗小鼠以及接受卡博替尼、抗PD-1或其联合治疗的小鼠的中位总生存期分别为28天、34天、34天和49天（<0.05）。RNA测序显示单药治疗后肺转移灶中成纤维细胞生长因子途径上调，而仅在联合治疗后观察到mTOR途径激活。mRCC中出现了治疗特异性的基因表达变化，这表明mRCC序贯治疗的最佳靶点因先前治疗而异。
