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

Ying Cao; Ruolan Qian; Ruilian Yao; Quan Zheng; Chen Yang; Xupeng Yang; Shuyi Ji; Linmen Zhang; Shujie Zhan; Yiping Wang; Tianshi Wang; Hui Wang; Chun-Ming Wong; Shengxian Yuan; Christopher Heeschen; Qiang Gao; René Bernards; Wenxin Qin; Cun Wang

doi:10.1016/j.devcel.2024.12.035

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. Online ahead of print.

Authors

Ying Cao¹, Ruolan Qian¹, Ruilian Yao², Quan Zheng³, Chen Yang¹, Xupeng Yang⁴, Shuyi Ji⁴, Linmen Zhang¹, Shujie Zhan¹, Yiping Wang⁵, Tianshi Wang⁶, Hui Wang¹, Chun-Ming Wong⁷, Shengxian Yuan⁸, Christopher Heeschen³, Qiang Gao⁴, René Bernards⁹, Wenxin Qin¹⁰, Cun Wang¹¹

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: [email protected].
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: [email protected].
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: [email protected].

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.