Cleavage of CAD by caspase-3 determines the cancer cell fate during chemotherapy

Jingsong Ma, Jiabao Zhao, Chensong Zhang, Jinshui Tan, Ao Cheng, Zhuo Niu, Zeyang Lin, Guangchao Pan, Chao Chen, Yang Ding, Mengya Zhong, Yifan Zhuang, Yubo Xiong, Huiwen Zhou, Shengyi Zhou, Meijuan Xu, Wenjie Ye, Funan Li (), Yongxi Song (), Zhenning Wang () and Xuehui Hong ()
Additional contact information
Jingsong Ma: Xiamen University
Jiabao Zhao: Xiamen University
Chensong Zhang: Xiamen University
Jinshui Tan: Xiamen University
Ao Cheng: The First Affiliated Hospital of China Medical University
Zhuo Niu: The First Affiliated Hospital of China Medical University
Zeyang Lin: Xiamen University
Guangchao Pan: Xiamen University
Chao Chen: Xiamen University
Yang Ding: Xiamen University
Mengya Zhong: Xiamen University
Yifan Zhuang: Xiamen University
Yubo Xiong: Xiamen University
Huiwen Zhou: Xiamen University
Shengyi Zhou: Xiamen University
Meijuan Xu: Xiamen University
Wenjie Ye: Xiamen University
Funan Li: Xiamen University
Yongxi Song: The First Affiliated Hospital of China Medical University
Zhenning Wang: The First Affiliated Hospital of China Medical University
Xuehui Hong: Xiamen University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60144-2

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