2. Academic Validation
  3. DYRK1A-TGF-β signaling axis determines sensitivity to OXPHOS inhibition in hepatocellular carcinoma

DYRK1A-TGF-β signaling axis determines sensitivity to OXPHOS inhibition in hepatocellular carcinoma

  • Dev Cell. 2025 Jan 7:S1534-5807(24)00775-5. doi: 10.1016/j.devcel.2024.12.035.
Ying Cao 1,  Ruolan Qian 1,  Ruilian Yao 2,  Quan Zheng 3,  Chen Yang 1,  Xupeng Yang 4,  Shuyi Ji 4,  Linmen Zhang 1,  Shujie Zhan 1,  Yiping Wang 5,  Tianshi Wang 6,  Hui Wang 1,  Chun-Ming Wong 7,  Shengxian Yuan 8,  Christopher Heeschen 3,  Qiang Gao 4,  René Bernards 9,  Wenxin Qin 10,  Cun Wang 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 5 Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 Department of Nephrology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7 State Key Laboratory for Liver Research and Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
  • 8 The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
  • 9 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: r.bernards@nki.nl.
  • 10 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: wxqin@sjtu.edu.cn.
  • 11 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: cwang@shsci.org.
PMID: 39798576 DOI: 10.1016/j.devcel.2024.12.035
Abstract

Intervening in mitochondrial Oxidative Phosphorylation (OXPHOS) has emerged as a potential therapeutic strategy for certain types of cancers. Employing kinome-based CRISPR screen, we find that knockout of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) synergizes with OXPHOS inhibitor IACS-010759 in liver Cancer cells. Targeting DYRK1A combined with OXPHOS inhibitors activates TGF-β signaling, which is crucial for OXPHOS-inhibition-triggered cell death. Mechanistically, upregulation of glutamine transporter solute carrier family 1 member 5 (SLC1A5) transcription compensates for the increased glutamine requirement upon OXPHOS inhibition. DYRK1A directly phosphorylates SMAD3 Thr132, thereby suppressing the negative impact of TGF-β signaling on transcription of SLC1A5, leading to intrinsic resistance of liver Cancer cells to OXPHOS inhibition. Moreover, we demonstrate the therapeutic efficacy of IACS-010759 in combination with DYRK1A inhibition in multiple liver Cancer models, including xenografts, patient-derived xenografts, and spontaneous tumor model. Our study elucidates how the DYRK1A-TGF-β signaling axis controls the response of tumor cells to OXPHOS inhibition and provides valuable insights into targeting OXPHOS for liver Cancer therapy.

Keywords

DYRK1A; IACS-010759; TGF-β signaling; hepatocellular carcinoma; oxidative phosphorylation.

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