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.

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.

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm* / genetics
  • Early Growth Response Protein 1* / genetics
  • Early Growth Response Protein 1* / metabolism
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • Feedback, Physiological
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lactic Acid* / metabolism
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mice
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Early Growth Response Protein 1
  • ErbB Receptors
  • EGFR protein, human
  • EGR1 protein, human
  • Protein Kinase Inhibitors
  • Lactic Acid