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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月30日

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  • 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,
  • Xuehui Hong

摘要

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.