Morozumi Kento, Kawasaki Yoshihide, Sakamoto Izumi, Sato Tomonori, Maekawa Masamitsu, Takasaki Shinya, Yamashita Shinichi, Mano Nariyasu, Ito Akihiro
Department of Urology, Tohoku Medical and Pharmaceutical University, Miyagi, Japan; Department of Urology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
Department of Urology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
Biomed Pharmacother. 2025 Oct;191:118492. doi: 10.1016/j.biopha.2025.118492. Epub 2025 Aug 29.
Tyrosine kinase inhibitors (TKIs) are key drugs in advanced renal cell carcinoma. Their prolonged efficacy is expected to translate directly into improved prognosis for patients with advanced renal cell carcinoma. In our previous studies, we identified important metabolic pathways related to sunitinib resistance. In this study, we examined whether TKI resistance could be overcome by controlling the glutamine metabolic pathway involved in sunitinib resistance. We established multiple renal cancer cell lines resistant to sunitinib and cabozantinib. We analyzed changes in the glutamine metabolic pathway associated with drug resistance. Furthermore, we inhibited the glutamine metabolic pathway using a glutaminase inhibitor (GLSi) and examined the antitumor effects of these TKIs on resistant renal cancer cells in vitro and in vivo. We also analyzed the mechanism of the antitumor effect of GLSi. In all established TKI-resistant cell lines, TKI resistance was associated with increased glutamine metabolism. GLSi showed significant antitumor effects on proliferation, invasion, and migration in all resistant cell lines. Immunostaining of resected TKI-resistant tumors demonstrated that GLSi-resistant TKIs exhibited sufficient antiangiogenic effects. VEGFR signal analysis suggested that the reduction of glutamate by GLSi activated PETN, which reduced VEGFR expression and its signaling, resulting in antitumor effects. GLSi has the potential to resensitize TKIs in TKI-resistant renal cancer cells. Therefore, controlling glutamine metabolism may extend the efficacy of existing TKIs and further improve the prognosis of patients with advanced renal cancer.
酪氨酸激酶抑制剂（TKIs）是晚期肾细胞癌的关键药物。它们的长期疗效有望直接转化为晚期肾细胞癌患者预后的改善。在我们之前的研究中，我们确定了与舒尼替尼耐药相关的重要代谢途径。在本研究中，我们研究了是否可以通过控制参与舒尼替尼耐药的谷氨酰胺代谢途径来克服TKI耐药。我们建立了多个对舒尼替尼和卡博替尼耐药的肾癌细胞系。我们分析了与耐药相关的谷氨酰胺代谢途径的变化。此外，我们使用谷氨酰胺酶抑制剂（GLSi）抑制谷氨酰胺代谢途径，并在体外和体内研究了这些TKIs对耐药肾癌细胞的抗肿瘤作用。我们还分析了GLSi抗肿瘤作用的机制。在所有建立的TKI耐药细胞系中，TKI耐药与谷氨酰胺代谢增加有关。GLSi对所有耐药细胞系的增殖、侵袭和迁移均显示出显著的抗肿瘤作用。对切除的TKI耐药肿瘤进行免疫染色表明，GLSi联合TKIs表现出足够的抗血管生成作用。VEGFR信号分析表明，GLSi使谷氨酸减少激活了PETN，从而降低了VEGFR表达及其信号传导，产生抗肿瘤作用。GLSi有可能使TKI耐药肾癌细胞对TKIs重新敏感。因此，控制谷氨酰胺代谢可能会延长现有TKIs的疗效，并进一步改善晚期肾癌患者的预后。
