Ma Jingsong, Zhao Jiabao, Zhang Chensong, Tan Jinshui, Cheng Ao, Niu Zhuo, Lin Zeyang, Pan Guangchao, Chen Chao, Ding Yang, Zhong Mengya, Zhuang Yifan, Xiong Yubo, Zhou Huiwen, Zhou Shengyi, Xu Meijuan, Ye Wenjie, Li Funan, Song Yongxi, Wang Zhenning, Hong Xuehui
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China.
Nat Commun. 2025 May 30;16(1):5006. doi: 10.1038/s41467-025-60144-2.
Metabolic heterogeneity resulting from the intra-tumoral heterogeneity mediates massive adverse outcomes of tumor therapy, including chemotherapeutic resistance, but the mechanisms inside remain largely unknown. Here, we find that the de novo pyrimidine synthesis pathway determines the chemosensitivity. Chemotherapeutic drugs promote the degradation of cytosolic Carbamoyl-phosphate synthetase II, Aspartate transcarbamylase, and Dihydroorotase (CAD), an enzyme that is rate-limiting for pyrimidine synthesis, leading to apoptosis. We also find that CAD needs to be cleaved by caspase-3 on its Asp1371 residue, before its degradation. Overexpressing CAD or mutating Asp1371 to block caspase-3 cleavage confers chemoresistance in xenograft and Cldn18-ATK gastric cancer models. Importantly, mutations related to Asp1371 of CAD are found in tumor samples that failed neoadjuvant chemotherapy and pharmacological targeting of CAD-Asp1371 mutations using RMY-186 ameliorates chemotherapy efficacy. Our work reveals the vulnerability of de novo pyrimidine synthesis during chemotherapy, highlighting CAD as a promising therapeutic target and biomarker.
肿瘤内异质性导致的代谢异质性介导了肿瘤治疗的大量不良后果，包括化疗耐药性，但其中的机制仍 largely 未知。在这里，我们发现从头嘧啶合成途径决定了化疗敏感性。化疗药物促进胞质天冬酰胺磷酸合成酶 II、天冬氨酸转氨甲酰酶和二氢乳清酸酶（CAD）的降解，CAD 是嘧啶合成的限速酶，导致细胞凋亡。我们还发现 CAD 需要在其 Asp1371 残基上被 caspase-3 切割，然后才会降解。在异种移植和 Cldn18-ATK 胃癌模型中，过表达 CAD 或将 Asp1371 突变以阻断 caspase-3 切割会赋予化疗耐药性。重要的是，在新辅助化疗失败的肿瘤样本中发现了与 CAD 的 Asp1371 相关的突变，并且使用 RMY-186 对 CAD-Asp1371 突变进行药理学靶向可改善化疗疗效。我们的工作揭示了化疗期间从头嘧啶合成的脆弱性，突出了 CAD 作为一个有前景的治疗靶点和生物标志物。
