2. Academic Validation
  3. NNMT promotes acquired EGFR-TKI resistance by forming EGR1 and lactate-mediated double positive feedback loops in non-small cell lung cancer

NNMT promotes acquired EGFR-TKI resistance by forming EGR1 and lactate-mediated double positive feedback loops in non-small cell lung cancer

  • Mol Cancer. 2025 Mar 15;24(1):79. doi: 10.1186/s12943-025-02285-y.
Jiali Dai # 1,  Xiyi Lu # 1,  Chang Zhang # 2,  Tianyu Qu # 1,  Wei Li 1,  Jun Su 3,  Renhua Guo 1,  Dandan Yin 4,  Pingping Wu 5,  Liang Han 6,  Erbao Zhang 7 8
Affiliations

Affiliations

  • 1 Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China.
  • 2 Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
  • 3 Department of Oncology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
  • 4 Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, Jiangsu, 210003, PR China. jsnydandan@sina.com.
  • 5 Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institue of Cancer Research, Nanjing, Jiangsu, PR China. pingpingwu_njmu@163.com.
  • 6 Department of Oncology, Xuzhou Central Hospital, Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, Jiangsu, PR China. hanliang_njmu@sina.com.
  • 7 Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. erbaozhang@njmu.edu.cn.
  • 8 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China. erbaozhang@njmu.edu.cn.
  • # Contributed equally.
PMID: 40089784 DOI: 10.1186/s12943-025-02285-y
Abstract

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are remarkably effective for treating EGFR-mutant non-small cell lung Cancer (NSCLC). However, patients inevitably develop acquired drug resistance, resulting in recurrence or metastasis. It is important to identify novel effective therapeutic targets to reverse acquired TKI resistance.

Results: Bioinformatics analysis revealed that nicotinamide N-methyltransferase (NNMT) was upregulated in EGFR-TKI resistant cells and tissues via EGR1-mediated transcriptional activation. High NNMT levels were correlated with poor prognosis in EGFR-mutated NSCLC patients, which could promote resistance to EGFR-TKIs in vitro and in vivo. Mechanistically, NNMT catalyzed the conversion of nicotinamide to 1-methyl nicotinamide by depleting S-adenosyl methionine (the methyl group donor), leading to a reduction in H3K9 trimethylation (H3K9me3) and H3K27 trimethylation (H3K27me3) and subsequent epigenetic activation of EGR1 and ALDH3A1. In addition, ALDH3A1 activation increased lactic acid levels, which further promoted NNMT expression via p300-mediated histone H3K18 lactylation on its promoter. Thus, NNMT mediates the formation of a double positive feedback loop via EGR1 and lactate, EGR1/NNMT/EGR1 and NNMT/ALDH3A1/lactate/NNMT. Moreover, the combination of a small-molecule inhibitor for NNMT (NNMTi) and osimertinib exhibited promising potential for the treatment of TKI resistance in an NSCLC osimertinib-resistant xenograft model.

Conclusions: The combined contribution of these two positive feedback loops promotes EGFR-TKI resistance in NSCLC. Our findings provide new insight into the role of histone methylation and histone lactylation in TKI resistance. The pivotal NNMT-mediated positive feedback loop may serve as a powerful therapeutic target for overcoming EGFR-TKI resistance in NSCLC.

Keywords

EGFR-TKI resistance; Histone lactylation; Histone methylation; Lung cancer.

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