bims-meluca 2025-10-19 papers

Sci Rep. 2025 Oct 13. 15(1): 35597

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

Alfred A Chan, Kamya Sankar, Karen L Reckamp, Begoña Díaz, Delphine J Lee.

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

DOI: https://doi.org/10.1038/s41598-025-11897-9

OMICS. 2025 Oct 16.

Integrative Transcriptomic and Metabolomic Analysis Reveals Aberrant Glycosylation as a Hallmark of Lung Adenocarcinoma.

Sanjukta Dasgupta.

Lung adenocarcinoma (LUAD) remains the most common subtype of lung cancer, characterized by high heterogeneity and poor survival outcomes. Although transcriptomic and metabolomic alterations have been individually studied, integrated multi-omics analyses are needed to uncover the convergent pathways that drive tumor progression. Differentially expressed genes (DEGs) were identified from the GSE229253 transcriptomic dataset comprising LUAD tumor and adjacent normal tissues, while significantly altered metabolites were obtained from the Lung Cancer Metabolome Database. The top 10 DEGs and metabolites were analyzed using the search tool for interacting chemicals (STITCH) to construct gene-metabolite networks, and Integrated Molecular Pathway Level Analysis (IMPaLA) was employed for integrated pathway enrichment to identify overlapping molecular processes. Transcriptomic profiling revealed 973 DEGs (410 upregulated and 563 downregulated), and metabolomic analysis identified significant alterations in metabolites linked to redox balance, amino acid derivatives, and nucleotide metabolism. Integration through STITCH generated a network of 16 nodes and 9 edges, highlighting gene-metabolite associations of probable biological relevance. Joint pathway enrichment analysis using IMPaLA consistently identified glycosylation-related pathways, particularly O-linked glycosylation of mucins, as major axes of convergence between transcriptomic and metabolomic alterations in LUAD (joint p = 0.00129-0.00434). Several genes (B3GNT6, FEZF1-AS1, and LCAL1) and metabolites (isoleucylleucine, leucylleucine, and isoleucylvaline) are probable novel candidates, warranting further investigation. These findings provide systems-level evidence that aberrant glycosylation is likely a central hallmark of LUAD, underscore the potential of glycosylation pathways as biomarkers and therapeutic targets, and demonstrate the utility of cross-omics approaches to unpack the molecular complexity of lung cancer.

Keywords: glycosylation; integrative analysis; lung adenocarcinoma; metabolomics; multi-omics biomarkers; transcriptomics

DOI: https://doi.org/10.1177/15578100251387518

J Clin Med. 2025 Sep 26. pii: 6826. [Epub ahead of print]14(19):

KRAS G12C Mutation Predicts Improved Survival in NSCLC Patients Receiving Immunotherapy: Insights from a Real-World Cohort.

Aslı Geçgel, Buket Şahin Çelik, Pınar Peker, Zeynep Sıla Gökdere, Didem Koca, Burçak Karaca, Deniz Nart, Erdem Göker.

Background: KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC), with KRAS G12C emerging as a therapeutically targetable subtype. However, the prognostic relevance of KRAS G12C compared with non-G12C mutations in patients receiving immune checkpoint inhibitors (ICIs) remains unclear. Methods: We retrospectively analyzed 80 NSCLC patients treated with ICIs between January 2020 and July 2024; data were censored on 3 July 2025. The cohort included 32 KRAS-mutant (20 G12C, 12 non-G12C) and 48 KRAS wild-type patients. Clinicopathological features, treatment details, and survival outcomes were collected. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, with group comparisons made using the log-rank test. Univariate and multivariate Cox regression analyses were conducted to identify independent prognostic factors. Results: Among 80 NSCLC patients treated with ICIs, the median OS and PFS were 14.3 and 8.2 months, respectively. Survival outcomes were comparable between KRAS-mutant and wild-type patients. Within the KRAS-mutant subgroup (n = 32), baseline characteristics were generally balanced between G12C (n = 20) and non-G12C (n = 12) cases, with non-significant trends toward higher metastatic burden and PD-L1 ≥ 50% in the G12C group. Median OS was significantly longer in G12C patients than in non-G12C patients (20.7 vs. 6.4 months; p = 0.021), whereas PFS did not differ significantly (10.2 vs. 3.7 months; p = 0.181). In multivariate analysis, non-G12C mutation independently predicted increased mortality risk (HR 3.35, 95% CI 1.26-8.89; p = 0.015). For PFS, recurrent disease status was associated with improved outcomes in univariate analysis (HR 0.30, 95% CI 0.09-0.94; p = 0.040), but no independent predictors were identified in multivariate modeling. Conclusions: In NSCLC patients treated with ICIs, the KRAS G12C mutation was associated with significantly improved OS compared with other KRAS subtypes, independent of clinicopathological characteristics. These findings suggest distinct biological behavior of KRAS variants in immunotherapy response and warrant further prospective validation.

Keywords: KRAS G12C mutation; immune checkpoint inhibitor; non-small cell lung cancer; overall survival

DOI: https://doi.org/10.3390/jcm14196826

Cancers (Basel). 2025 Oct 04. pii: 3230. [Epub ahead of print]17(19):

Lack of Association Between Glucose Homeostasis and Immune Checkpoint Inhibitor Outcomes: A Retrospective Institutional Review.

Joy Justice, Hannah Burnette, Rebecca Irlmeier, Fei Ye, Douglas B Johnson.

BACKGROUND/OBJECTIVES: Immune checkpoint inhibitors (ICIs) have revolutionized outcomes for patients with melanoma. As such, it is important to understand factors that may influence response as well as toxicity to these therapies. Impaired glucose control is often a sign of pathologic inflammation and may alter immune system regulation, but it is unclear whether glucose control impacts patients with melanoma on ICIs.
METHODS: After reviewing patients with melanoma treated with ICIs at our institution between 2014 and 2024, we assessed whether longitudinal glucose control is associated with patient outcomes (response, progression-free survival, overall survival, and treatment toxicity) during ICI therapy.
RESULTS: There was no significant difference in baseline glucose values between responders and non-responders (102.5 vs. 106.0, p = 0.093). Having a baseline glucose over 200 or any glucose over 200 was not significantly associated with response (p = 0.79, p = 0.20), progression-free survival (p = 0.64, p = 0.45), overall survival (p = 0.56, p = 0.36), or toxicity (p = 0.29, p = 0.11). Although a diagnosis of diabetes mellitus was not significantly associated with response (p = 0.84), progression-free survival (p = 0.12), or toxicity (p = 0.11), it was associated with improved overall survival (p = 0.0034) in the small number of patients with diabetes.
CONCLUSIONS: Overall, we observed that glucose control was not strongly associated with efficacy or toxicity in patients treated with ICIs.

Keywords: CTLA-4; PD-1; immune checkpoint inhibitors; immunotherapy; metastatic melanoma; patient outcome; treatment toxicity

DOI: https://doi.org/10.3390/cancers17193230