Elevated co-expression of TIMM17A and NMT1 is associated with poor survival in non-small cell lung cancer

Sci Rep. 2025 Oct 13;15(1):35597. doi: 10.1038/s41598-025-11897-9.

Abstract

Lung carcinoma cells harboring mutations in STK11 and/or KEAP1 in a KRAS mutant background have intrinsic therapeutic resistance. We found that these cells are sensitive to preclinical stage pharmacological inhibitors of N-myristoyltransferases, which reduce tumor growth in xenograft mouse models. Unexpectedly, the sensitivity to NMT inhibitors correlates with cell's dependency on the inner mitochondrial protein Translocase of Inner Mitochondrial Membrane 17 A (Protein: TIM17A, Gene: TIMM17A). Leveraging data from The Cancer Genome Atlas (TCGA), we set to further explore the significance of N-myristoyltransferase-1 (NMT1) and TIMM17A expression individually and together in cox-regression models to test their association to clinical endpoints in lung carcinoma. Our results showed that lung adenocarcinoma (LUAD) tissue with high expression of both NMT1 and TIMM17A had worse overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) compared to those with low expression of both genes. Moreover, high NMT1 was associated with worse OS, but only in the group with also high TIMM17A. This highlights a novel NMT1/TIMM17A axis as a promising pathway for predicting patient prognosis. Further studies are warranted investigating both genes as targets for novel therapeutic strategies for KRAS mutant non-small cell lung carcinoma with STK11 and/or KEAP1 co-mutations.

Keywords: Lung adenocarcinoma; NMT1; Survival; TIMM17A; The Cancer Genome Atlas.

MeSH terms

  • Acyltransferases* / genetics
  • Acyltransferases* / metabolism
  • Adenocarcinoma of Lung / genetics
  • Animals
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / mortality
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / mortality
  • Lung Neoplasms* / pathology
  • Male
  • Mice
  • Mitochondrial Precursor Protein Import Complex Proteins* / genetics
  • Prognosis

Substances

  • Mitochondrial Precursor Protein Import Complex Proteins
  • Acyltransferases
  • Kelch-Like ECH-Associated Protein 1
  • KEAP1 protein, human