LKB1 inactivation elicits an NNMT-mediated methyl sink and confers dependence on PRMT5 in lung cancer

  • Cell Rep. 2026 Jun 23;45(6):117487. doi: 10.1016/j.celrep.2026.117487.
Wen Mi  1 ,  Xinyi Xia  1 ,  Yun Xue  2 ,  Liucheng Li  1 ,  Li Yang  3 ,  Xincheng Yang  3 ,  Jie Xu  3 ,  Xinlei Cai  4 ,  Yijia Zhou  2 ,  Lingzhi Zhu  1 ,  Guanlin Wang  1 ,  Fei Li  4 ,  Hongbin Ji  2 ,  Xinyuan Tong  5 ,  Pingyu Liu  6 ,  Fuming Li  7
Affiliations
  • 1. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China.
  • 2. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
  • 3. Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai 201203, China.
  • 4. Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China; Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 5. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Institute of Thoracic Oncology & Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: [email protected].
  • 6. Research and Innovation Center, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 7. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China. Electronic address: [email protected].
PMID: 42234565 DOI: 10.1016/j.celrep.2026.117487
Abstract

The protein arginine methyl transferase 5 (PRMT5) emerges as a therapeutic target in S-methyl-5'-thioadenosine Phosphorylase (MTAP)-deleted cancers, where 5'-methylthioadenosine (MTA) accumulation partially inhibits its activity. However, it remains unclear whether Other genetic alterations can dictate PRMT5 activity in Cancer. Here, we identify liver kinase B1 (LKB1) as an alternative predictor of PRMT5 inhibition in lung Cancer independent of MTAP. Mechanistically, LKB1 loss activates salt-inducible kinase 1/2 (SIK1/2)-cAMP response element-binding protein-regulated transcription coactivator 2 (CRTC2) signaling to upregulate nicotinamide N-methyltransferase (NNMT), creating a "methyl sink" that lowers the S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) ratio and attenuates PRMT5 activity. NNMT overexpression is sufficient to induce this hypomorphic PRMT5 state and heighten sensitivity to PRMT5 inhibitors. Functionally, PRMT5 inhibition induces senescence in LKB1-deficient cells and confers vulnerability to navitoclax, synergistically blunting tumor growth in vivo. Collectively, we identify PRMT5 as an actionable therapeutic vulnerability in LKB1-deficient lung Cancer, and propose LKB1 status/NNMT expression as potential biomarkers for PRMT5 inhibition. These findings may expand the clinical utility of PRMT5-targeted therapies beyond MTAP-deleted cancers.

Keywords
CP: cancer; LKB1; NNMT; PRMT5; methyl sink; senescence.
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