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

  • Nat Commun. 2025 May 30;16(1):5006. doi: 10.1038/s41467-025-60144-2.
Jingsong Ma  #  1  2 ,  Jiabao Zhao  #  3 ,  Chensong Zhang  3 ,  Jinshui Tan  1  2 ,  Ao Cheng  4 ,  Zhuo Niu  4 ,  Zeyang Lin  5 ,  Guangchao Pan  1  2 ,  Chao Chen  6 ,  Yang Ding  6 ,  Mengya Zhong  7 ,  Yifan Zhuang  1 ,  Yubo Xiong  1  2 ,  Huiwen Zhou  1  2 ,  Shengyi Zhou  1  2 ,  Meijuan Xu  1  2 ,  Wenjie Ye  1  2 ,  Funan Li  8 ,  Yongxi Song  9 ,  Zhenning Wang  10 ,  Xuehui Hong  11  12
Affiliations
  • 1. Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 2. Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China.
  • 3. State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University, Xiamen, China.
  • 4. Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China.
  • 5. Department of Pathology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 6. Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
  • 7. Department of Radiology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 8. Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China. [email protected].
  • 9. Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China. [email protected].
  • 10. Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China. [email protected].
  • 11. Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. [email protected].
  • 12. Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China. [email protected].
  • # Contributed equally.
PMID: 40442064 DOI: 10.1038/s41467-025-60144-2
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.

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