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

TL;DR

High levels of TIMM17A and NMT1 in lung cancer are linked to worse survival, suggesting a new target for treatment.

Contribution

Identifies a novel NMT1/TIMM17A axis as a potential prognostic and therapeutic target in specific lung cancer subtypes.

Findings

High NMT1 and TIMM17A expression correlates with worse overall, disease-specific, and disease-free survival in lung adenocarcinoma.

High NMT1 expression is only associated with poor survival when TIMM17A is also highly expressed.

NMT inhibitors show preclinical efficacy in tumors with STK11/KEAP1 and KRAS mutations.

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.

The online version contains supplementary material available at 10.1038/s41598-025-11897-9.

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