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Series GSE272045

Query DataSets for GSE272045

Status

Public on Jul 16, 2024

Title

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

Organism

Homo sapiens

Experiment type

Expression profiling by array

Summary

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).

Overall design

Gene expression was examined in shRNA-mediated mutant KRAS-silenced and KRAS-retained NSCLC cell lines harboring KRAS-G12C (H23, H358, and H1792) or KRAS-G12V (H441) mutations. Mutant KRAS expressions in these NSCLC cells were silenced with mutant KRAS-specific shRNA vectors. The H1299 NSCLC cell line was used as a KRAS non-mutated control. For HBEC samples, mutant KRAS-G12V transduction was mediated by the mutant KRAS-V12V expression vector, whereas p53 expression was silenced by the shRNA vector targeting the TP53 gene in the HBEC3 immortalized human bronchial epithelial cell line, which was established by hTERT and Cdk4 gene transduction. Gene expression was examined in mutant KRAS-G12V-expressing or mutant KRAS-nonexpressing HBEC3 cells with or without shRNA-mediated p53 knockdown. H23-Ctrl: H23 with control shRNA; H23-KRAS-C12: H23 with shRNA targeting mutant KRAS-G12C; H358-Ctrl: H358 with control shRNA; H358-KRAS-C12: H358 with shRNA targeting mutant KRAS-G12C; H1792-Ctrl: H1792 with control shRNA; H1792-KRAS-C12: H1792 with shRNA targeting mutant KRAS-G12C; H441-Ctrl: H441 with control shRNA; H441-KRAS-V12: H441 with shRNA targeting mutant KRAS-G12V; H1299-Ctrl: H1299 with control shRNA; H1299-KRAS-C12: H1299 with shRNA targeting mutant KRAS-G12C; H1299-KRAS-V12: H1299 with shRNA targeting mutant KRAS-G12V; HBEC3: the immortalized human bronchial epithelial cell line, which harbors wild-type KRAS and retains p53 expression; HBEC3-K: HBEC3 expressing mutant KRAS-G12V; HBEC3-p53: HBEC with p53 knockdown; HBEC3-p53K: HBEC3 with p53 knockdown but expressing mutant KRAS-G12V.

Contributor(s)

Sunaga N, Girard L, Sato M

Citation(s)

21306997

Submission date

Jul 11, 2024

Last update date

Jul 17, 2024

Contact name

Noriaki Sunaga

E-mail(s)

[email protected]