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Cited by 6Lung Cancer Treatments and MutationsLung Cancer Research StudiesCancer Genomics and Diagnostics

Integrative proteomic characterization of human lung adenocarcinoma with KRAS G12 mutations reveals molecular pathogenesis

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Shi, Xinyu, Hu, Liling, Huang, Yongshi, Zhang, Mei-Fang, Ying, Xingfeng, Yuan, Xiaoyi, Wen, Nengqiao, Lu, Jiangli +6 more·2026·Journal of Advanced Research
DOI 10.1016/j.jare.2025.09.014PMC PMC13227296
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Abstract

INTRODUCTION: Integrated proteogenomic studies of lung adenocarcinoma (LUAD) have provided unique insights with potential clinical effects. Comprehensive proteomic analyses are needed to better understand the molecular landscape of LUAD with KRAS G12 mutations. OBJECTIVES: This study aims to characterize the proteogenomic profile of LUAD with KRAS G12 mutation variants. METHODS: We performed next-generation sequencing (NGS) on 9,479 solid tumors, including 3,523 lung cancers. Proteomic profiling was conducted on 96 LUAD patients with KRAS G12 mutations or wild-type status using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LUAD tumor immune microenvironment (TIME) was characterized by multiplex immunohistochemistry (mIHC), and protein-protein interactions (PPIs) in KRAS G12-mutant lung cancer cells were mapped using biotin-based proximity labeling. RESULTS: Genomic analysis revealed heterogeneous KRAS-informed mutational profiles across pan-cancer and lung cancer, with allele-specific resolution for KRAS G12 mutations. Proteomic profiling of KRAS G12-mutant LUAD delineated distinct molecular features and tumor progression hallmarks. Unsupervised clustering identified three molecular subtypes, with the immune modulation subtype (S2) characterized by KRAS G12C enrichment, aggressive clinical features, and the greatest potential benefit from immunotherapy. The immune landscape of LUAD showed increased immune cell infiltration in KRAS G12C-mutant tumors. Additionally, proximal proteomics mapped a landscape of gain-of-interactions driven by KRAS G12 mutations, with ion transporter SLC4A7 emerged as a potential effector in immune modulation in the G12C variant. CONCLUSIONS: This comprehensive proteogenomic study provides insights into the molecular features of LUAD harboring KRAS G12 mutations, which may inform patient stratification and potential therapeutic approaches, pending further clinical validation.

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  • Significant interpatient differences exist in molecular characteristics, tumor progression dynamics, and treatment sensitivity in LUAD, posing major challenges to standardized treatment strategies.

    “Significant interpatient differences exist in molecular characteristics, tumor progression dynamics, and treatment sensitivity, posing major challenges to standardized treatment strategies (6, 7).”

    From Bioinformatics-based identification of glycolysis-related signatures associated with drug resistance and prognosis in lung adenocarcinoma (2026) · cites this paper as [7]

    The Results and Discussion describe molecular differences and different rates of progression among KRAS G12-mutant LUAD subtypes, and argue for tailored treatment strategies. The Results associate subtype signatures with immunotherapy response, but the Discussion says treatment responses were not directly assessed. Thus, the paper supports heterogeneity within the studied group, not the claim of established interpatient differences in treatment sensitivity across LUAD generally. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Shi, X., Hu, L., Huang, Y., Zhang, M.-F., Ying, X., Yuan, X., Wen, N., Lu, J., Zou, H., Tan, X., He, Q.-Y., Wang, F., Yang, H., & Zhang, C. Z.
Affiliations
  • Jinan University (CN)
  • Sun Yat-sen University Cancer Center (CN)
  • Sun Yat-sen University (CN)
Corresponding author
  • Zhang, Mei-Fang
  • Wang, Fang
  • Yang, Hong
  • Zhang, Chris Zhiyi
ORCID
Venue
Journal of Advanced Research
Publisher
Elsevier BV
Published
2026-06
Volume
84
Pages
675-693
ISSN
  • 2090-1224 (ISSN-L)
  • 2090-1232
DOI
10.1016/j.jare.2025.09.014
PMC
PMC13227296
OpenAlex
W4414189878
Cited by
6
References
8
Citations by year
2026: 4 · 2025: 2
FWCI
3.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Advanced Research (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
Funders
  • Fundamental Research Funds for the Central Universities (21624109)
  • National Key Research and Development Program of China (2022YFA1304604)
  • National Natural Science Foundation of China (82273110, 82273032)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
lung adenocarcinoma, KRAS G12C, proteogenomics, tumor immune microenvironment, immune cell infiltration, protein-protein interaction, SLC4A7, molecular subtypes, immunotherapy response, patient stratification
MeSH terms
Adenocarcinoma of Lung, Female, Humans, Lung Neoplasms, Male, Mutation, Proto-Oncogene Proteins p21(ras), Proteomics, Tandem Mass Spectrometry, High-Throughput Nucleotide Sequencing, Tumor Microenvironment

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