Liu Jinwen, Huang Gaowei, Lin Hao, Yang Rui, Zhan Wenhao, Luo Cheng, Wu Yukun, Chen Lingwu, Mao Xiaopeng, Chen Junxing, Huang Bin
Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Urology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
Cancer Res. 2025 Mar 14;85(6):1113-1129. doi: 10.1158/0008-5472.CAN-24-0050.
Sunitinib is a first-line targeted therapy for patients with renal cell carcinoma (RCC), but resistance represents a significant obstacle to the treatment of advanced and metastatic RCC. Metabolic reprogramming is a characteristic of RCC, and changes in metabolic processes might contribute to resistance to sunitinib. In this study, we identified methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme involved in one-carbon metabolism, as a critical mediator of sunitinib resistance in RCC. MTHFD2 was elevated in sunitinib-resistant RCC cells, and loss of MTHDF2 conferred sensitivity to sunitinib. In patients, MTHFD2 was highly expressed in RCC and was associated with poor outcomes. Mechanistically, MTHFD2 stimulated UDP-N-acetylglucosamine (UDP-GlcNAc) biosynthesis and promoted cMYC O-GlcNAcylation by driving the folate cycle. O-GlcNAcylation enhanced cMYC stability and promoted MTHFD2 and cyclin D1 transcription. Targeting MTHFD2 or cyclin D1 sensitized tumor cells to sunitinib in vitro and in vivo. Consistently, development of a peptide drug capable of efficiently degrading MTHFD2 enabled reversal of sunitinib resistance in RCC. These findings identify a noncanonical metabolic function of MTHFD2 in cell signaling and response to therapy and reveal the interplay between one-carbon metabolism and sunitinib resistance in RCC. Targeting MTHFD2 could be an effective approach to overcome sunitinib resistance. Significance: MTHFD2 regulates cMYC O-GlcNAcylation to promote sunitinib resistance in renal cell carcinoma, highlighting the important role of one-carbon metabolism in sunitinib resistance and proposing therapeutic strategies to improve patient outcomes.
舒尼替尼是肾细胞癌（RCC）患者的一线靶向治疗药物，但耐药性是晚期和转移性RCC治疗的重大障碍。代谢重编程是RCC的一个特征，代谢过程的变化可能导致对舒尼替尼的耐药性。在本研究中，我们确定亚甲基四氢叶酸脱氢酶2（MTHFD2），一种参与一碳代谢的线粒体酶，是RCC中舒尼替尼耐药的关键介质。MTHFD2在舒尼替尼耐药的RCC细胞中升高，而MTHDF2的缺失赋予对舒尼替尼的敏感性。在患者中，MTHFD2在RCC中高表达，并与不良预后相关。机制上，MTHFD2通过驱动叶酸循环刺激UDP-N-乙酰葡糖胺（UDP-GlcNAc）生物合成并促进cMYC的O-连接N-乙酰葡糖胺化。O-连接N-乙酰葡糖胺化增强cMYC稳定性并促进MTHFD2和细胞周期蛋白D1转录。靶向MTHFD2或细胞周期蛋白D1在体外和体内使肿瘤细胞对舒尼替尼敏感。一致地，开发一种能够有效降解MTHFD2的肽药物能够逆转RCC中的舒尼替尼耐药性。这些发现确定了MTHFD2在细胞信号传导和治疗反应中的非经典代谢功能，并揭示了一碳代谢与RCC中舒尼替尼耐药之间的相互作用。靶向MTHFD2可能是克服舒尼替尼耐药的有效方法。意义：MTHFD2调节cMYC的O-连接N-乙酰葡糖胺化以促进肾细胞癌中的舒尼替尼耐药，突出了一碳代谢在舒尼替尼耐药中的重要作用，并提出了改善患者预后的治疗策略。
