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Deep Sequence Analysis of non-small cell lung cancer: Integrated analysis of gene expression, alternative splicing, and single nucleotide variations in lung adenocarcinomas with and without oncogenic KRAS mutations

ABSTRACT: In this manuscript, we have used RNA-Sequencing experiment to obtain and integrate a variety of genomic features in order to identify signaling pathways that are associated to mutant KRAS lung tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE34914 | GEO | 2012/06/08

SECONDARY ACCESSION(S): PRJNA150161

REPOSITORIES: GEO

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Deep Sequence Analysis of non-small cell lung cancer: Integrated analysis of gene expression, alternative splicing, and single nucleotide variations in lung adenocarcinomas with and without oncogenic KRAS mutations

Project description:In this manuscript, we have used RNA-Sequencing experiment to obtain and integrate a variety of genomic features in order to identify signaling pathways that are associated to mutant KRAS lung tumors. 8 lung adenocarcinomas with mutant KRAS in lung tumors and 8 lung adenocarcarcinomas without KRAS mutation of which one sample is ran twice for QC purposes.

2012-06-07 | E-GEOD-34914 | biostudies-arrayexpress

Deep Sequence Analysis of Non-Small Cell Lung Cancer: Integrated Analysis of Gene Expression, Alternative Splicing, and Single Nucleotide Variations in Lung Adenocarcinomas with and without Oncogenic KRAS Mutations.

Project description:KRAS mutations are highly prevalent in non-small cell lung cancer (NSCLC), and tumors harboring these mutations tend to be aggressive and resistant to chemotherapy. We used next-generation sequencing technology to identify pathways that are specifically altered in lung tumors harboring a KRAS mutation. Paired-end RNA-sequencing of 15 primary lung adenocarcinoma tumors (8 harboring mutant KRAS and 7 with wild-type KRAS) were performed. Sequences were mapped to the human genome, and genomic features, including differentially expressed genes, alternate splicing isoforms and single nucleotide variants, were determined for tumors with and without KRAS mutation using a variety of computational methods. Network analysis was carried out on genes showing differential expression (374 genes), alternate splicing (259 genes), and SNV-related changes (65 genes) in NSCLC tumors harboring a KRAS mutation. Genes exhibiting two or more connections from the lung adenocarcinoma network were used to carry out integrated pathway analysis. The most significant signaling pathways identified through this analysis were the NF?B, ERK1/2, and AKT pathways. A 27 gene mutant KRAS-specific sub network was extracted based on gene-gene connections from the integrated network, and interrogated for druggable targets. Our results confirm previous evidence that mutant KRAS tumors exhibit activated NF?B, ERK1/2, and AKT pathways and may be preferentially sensitive to target therapeutics toward these pathways. In addition, our analysis indicates novel, previously unappreciated links between mutant KRAS and the TNFR and PPAR? signaling pathways, suggesting that targeted PPAR? antagonists and TNFR inhibitors may be useful therapeutic strategies for treatment of mutant KRAS lung tumors. Our study is the first to integrate genomic features from RNA-Seq data from NSCLC and to define a first draft genomic landscape model that is unique to tumors with oncogenic KRAS mutations.

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cAMP response element-binding protein mediates immune-evasion of KRAS-mutant lung adenocarcinomas

Project description:We discovered that KRAS-mutant lung adenocarcinomas (LADC) co-opt CREB in order to evade the innate immune system: KRAS-driven CREB activation in LADC suppresses the expression of CXCR1 ligands that would otherwise recruit neutrophils to the tumor site. CREB was overexpressed in murine KRAS-mutant LADC, pulmonary Creb1-deletion inhibited disease development, and Creb1-overexpression boosted the tumorigenicity of KRAS-mutant cells. Conditional Creb1 deletion in Kras-mutant LADC cells caused overexpression of CXCR1/2 ligands, and lung tumor-bearing Creb1-deleted mice displayed increased pulmonary neutrophils. Cxcr1-deficient mice were selectively permissive to KRAS-mutant tumor growth and showed defective neutrophil recruitment. The pro-tumor effects of CREB required intact host-Cxcr1 and those of host-Cxcr1 necessitated mutant KRAS in cancer cells. Pharmacologic CREB blockade prevented tumor growth and restored neutrophil recruitment only when initiated before immune evasion of KRAS-mutant LADC cells. CREB and CXCR1 expression were respectively restricted to tumor and stromal cells of human LADC, while CREB-controlled genes profoundly impacted survival. In summary, CREB-mediated immune evasion of KRAS-mutant LADC rests on signaling to myeloid CXCR1 and is actionable.

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Murine Kras mutant or Kras wildtype cancer cell lines

Project description:Comparison of gene expression in murine Kras mutant (LLC, AE17, MC38, FULA1) and Kras wildtype cell lines (B16F10, PANO2, CULA). First gene expression of benign cells and tissue ( BMDM, TEC, LUNG, BMMC) was subtracted from both Kras mutant or Kras wildtype gene expression profiles. Second Kras mutant gene expression was compared to Kras wildtype gene expression. Cell lines expressing genetically modified Kras gene were included in the analysis. Genetic modification was either done by overexpression of mutant KRAS harboring a G12C mutation or silencing with shRNA targeting Kras. shControl cell lines were used also as wildtype samples in different analysis presented in the manuscript except MC38 ( run on chip MoGene_1.0).

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Project description:Oncogenic KRAS mutations are a key driver for initiation and progression in non-small-cell lung cancer (NSCLC). However, how post-translational modifications (PTMs) of KRAS, especially methylation, modify KRAS activity remain largely unclear. Here, we show that SET domain containing histone lysine methyltransferase 7 (SETD7) interacts with KRAS and methylates KRAS at lysines 182 and 184. SETD7-mediated methylation of KRAS leads to degradation of KRAS and attenuation of the RAS/MEK/ERK signaling cascade, endowing SETD7 with a potent tumor-suppressive role in NSCLC, both in vitro and in vivo. Mechanistically, RABGEF1, a ubiquitin E3 ligase of KRAS, was recruited and promoted KRAS degradation in a K182/K184 methylation-dependent manner. Notably, SETD7 is inversely correlated with KRAS at the protein level in clinical NSCLC tissues. Low SETD7 or RABGEF1 expression is associated with poor prognosis in lung adenocarcinoma patients. Altogether, our results elucidate a tumor-suppressive function of SETD7 that operates via modulating KRAS methylation and degradation.

2023-07-19 | PXD043931 |

Expression data from 36 KRAS-mutant lung adenocarcinomas from the BATTLE-2 clinical trial.

Project description:In this dataset, we include expression data from 36 KRAS-mutant lung adenocarcinomas from Stage 1 of the BATTLE-2 trial, reflecting patients whose disease has relapsed or progresses following at least one front-line metastatic chemotherapy regimen. Tumor biopsy was performed following informed consent and prior to randomisation to one of the four possible treatment arms.

2015-10-01 | GSE61913 | GEO

Low-frequency KRAS mutations are prevalent in lung adenocarcinomas.

Project description:This study quantified low-frequency KRAS mutations in normal lung and lung adenocarcinomas, to understand their potential significance in the development of acquired resistance to EGFR-targeted therapies.Allele-specific Competitive Blocker-PCR was used to quantify KRAS codon 12 GAT (G12D) and GTT (G12V) mutation in 19 normal lung and 21 lung adenocarcinoma samples.Lung adenocarcinomas had KRAS codon 12 GAT and GTT geometric mean mutant fractions of 1.94 × 10-4 and 1.16 × 10-3, respectively. For 76.2% of lung adenocarcinomas, the level of KRAS mutation was greater than the upper 95% confidence interval of that in normal lung.KRAS mutant tumor subpopulations, not detectable by DNA sequencing, may drive resistance to EGFR blockade in lung adenocarcinoma patients.

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Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas.

Project description:KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.

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Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas.

Project description:KRAS mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) KRAS on druggable targets can uncover new vulnerabilities for the treatment of KRAS mutant lung adenocarcinomas. Using commercially available KRAS mutant lung adenocarcinoma cell lines, we explored the influence of WT KRAS on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the KRAS WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the KRAS WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT KRAS impacts on signaling events and druggable targets in KRAS mutant lung adenocarcinomas.

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