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Identification of mutant KRAS-related genes associated with malignant phenotypes in NSCLC

ABSTRACT: Oncogenic KRAS is found in more than 25% of lung adenocarcinomas, the major histologic subtype of non–small cell lung cancer (NSCLC), and is an important target for drug development. To this end, we generated four NSCLC lines with stable knockdown selective for oncogenic KRAS. As expected, stable knockdown of oncogenic KRAS led to inhibition of in vitro and in vivo tumor growth in the KRAS-mutant NSCLC cells, but not in NSCLC cells that have wild-type KRAS (but mutant NRAS). Surprisingly, we did not see large-scale induction of cell death and the growth inhibitory effect was not complete. To further understand the ability of NSCLCs to grow despite selective removal of mutant KRAS expression, we conducted microarray expression profiling of NSCLC cell lines with or without mutant KRAS knockdown and isogenic human bronchial epithelial cell lines with and without oncogenic KRAS. We found that although the mitogen-activated protein kinase pathway is significantly downregulated after mutant KRAS knockdown, these NSCLCs showed increased levels of phospho-STAT3 and phospho–epidermal growth factor receptor, and variable changes in phospho-Akt. In addition, mutant KRAS knockdown sensitized the NSCLCs to p38 and EGFR inhibitors. Our findings suggest that targeting oncogenic KRAS by itself will not be sufficient treatment, but may offer possibilities of combining anti-KRAS strategies with other targeted drugs. Detailed information on the microarray results are available in a previous study (Sunaga N, et al. Mol Cancer Ther. 2011;10:336-46).

ORGANISM(S): Homo sapiens

PROVIDER: GSE272045 | GEO | 2024/07/16

REPOSITORIES: GEO

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Project description:Non-small cell lung cancer (NSCLC) cell lines are widely used model systems to study molecular aspects of lung cancer. Comparative and in-depth proteome expression data across many NSCLC cell lines has not been generated yet, but would be of utility for the investigation of candidate targets and markers in oncogenesis. We employed a SILAC reference approach to perform replicate proteome quantifications across 23 distinct NSCLC cell lines. On average, close to 4000 distinct proteins were identified and quantified per cell line. These included many known targets and diagnostic markers, indicating that our proteome expression data represents a useful resource for NSCLC pre-clinical research. To assess proteome diversity within the NSCLC cell line panel, we performed hierarchical clustering and principal component analysis of proteome expression data. Our results indicate that general proteome diversity among NSCLC cell lines supersedes potential effects common to K-Ras or epidermal growth factor receptor (EGFR) oncoprotein expression. However, we observed partial segregation of EGFR or KRAS mutant cell lines for certain principal components, which reflected biological differences according to gene ontology enrichment analyses. Moreover, statistical analysis revealed several proteins that were significantly overexpressed in KRAS or EGFR mutant cell lines. Biological significance Despite enormous progress in molecular characterization and targeted therapy NSCLC represents a major cause for cancer-related deaths. While pre-clinical models such as NSCLC cell lines have been studied on the genomic and transcriptional level, proteome composition is poorly characterized. We conducted quantitative profiling across 23 NSCLC cell lines and studied global proteome diversity in relation to the presence of oncogenic KRAS or EGFR mutations. Notably, in-depth bioinformatics analysis pointed to prominent biological processes as well as up-regulated proteins in KRAS and EGFR mutant cells, highlighting the utility of cancer cell proteomics to identify target or biomarker candidates in the context of specific oncogenic mechanisms.

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Identification of mutant KRAS-related genes associated with malignant phenotypes in NSCLC

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