Dataset Information

Transcriptional profiling of non-small cell lung cancer cells with activating EGFR somatic mutations.

ABSTRACT:

Background

Activating somatic mutations in epidermal growth factor receptor (EGFR) confer unique biologic features to non-small cell lung cancer (NSCLC) cells, but the transcriptional mediators of EGFR in this subgroup of NSCLC have not been fully elucidated.

Methodology/principal findings

Here we used genetic and pharmacologic approaches to elucidate the transcriptomes of NSCLC cell lines. We transcriptionally profiled a panel of EGFR-mutant and -wild-type NSCLC cell lines cultured in the presence or absence of an EGFR tyrosine kinase inhibitor. Hierarchical analysis revealed that the cell lines segregated on the basis of EGFR mutational status (mutant versus wild-type), and expression signatures were identified by supervised analysis that distinguished the cell lines based on mutational status (wild-type versus mutant) and type of mutation (L858R versus Delta746-750). Using an EGFR mutation-specific expression signature as a probe, we mined the gene expression profiles of two independent cohorts of NSCLC patients and found the signature in a subset. EGFR tyrosine kinase inhibitor treatment regulated the expression of multiple genes, and pharmacologic inhibition of the protein products of two of them (PTGS2 and EphA2) inhibited anchorage-independent growth in EGFR-mutant NSCLC cells.

Conclusions/significance

We have elucidated genes not previously associated with EGFR-mutant NSCLC, two of which enhanced the clonogenicity of these cells, distinguishing these mediators from others previously shown to maintain cell survival. These findings have potential clinical relevance given the availability of pharmacologic tools to inhibit the protein products of these genes.

SUBMITTER: Choi K

PROVIDER: S-EPMC2080626 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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Publications

Transcriptional profiling of non-small cell lung cancer cells with activating EGFR somatic mutations.

Choi Kuicheon K Creighton Chad J CJ Stivers David D Fujimoto Nobukazu N Kurie Jonathan M JM

PloS one 20071121 11

<h4>Background</h4>Activating somatic mutations in epidermal growth factor receptor (EGFR) confer unique biologic features to non-small cell lung cancer (NSCLC) cells, but the transcriptional mediators of EGFR in this subgroup of NSCLC have not been fully elucidated.<h4>Methodology/principal findings</h4>Here we used genetic and pharmacologic approaches to elucidate the transcriptomes of NSCLC cell lines. We transcriptionally profiled a panel of EGFR-mutant and -wild-type NSCLC cell lines cultur ...[more]

PMID: 18030354

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Project description:Non-small cell lung cancer (NSCLC) cells harboring activating mutations of the epidermal growth factor receptor (EGFR) tend to display elevated activity of several survival signaling pathways. Surprisingly, these mutations also correlate with reduced phosphorylation of ERK and SHP2, a protein tyrosine phosphatase required for complete ERK activation downstream of most receptor tyrosine kinases. As ERK activity influences cellular response to EGFR inhibition, altered SHP2 function could have a role in the striking response to gefitinib witnessed with EGFR mutation. Here, we demonstrate that impaired SHP2 phosphorylation correlates with diminished SHP2 function in NSCLC cells expressing mutant, versus wild-type, EGFR. In NSCLC cells expressing wild-type EGFR, SHP2 knockdown decreased ERK phosphorylation, basally and in response to gefitinib, and increased cellular sensitivity to gefitinib. In cells expressing EGFR mutants, these effects of SHP2 knockdown were less substantial, but the expression of constitutively active SHP2 reduced cellular sensitivity to gefitinib. In cells expressing EGFR mutants, which do not undergo efficient ligand-mediated endocytosis, SHP2 was basally associated with GRB2-associated binder 1 (GAB1) and EGFR, and SHP2's presence in membrane fractions was dependent on EGFR activity. Whereas EGF promoted a more uniform intracellular distribution of initially centrally localized SHP2 in cells expressing wild-type EGFR, SHP2 was basally evenly distributed and did not redistribute in response to EGF in cells with EGFR mutation. Thus, EGFR mutation may promote association of a fraction of SHP2 at the plasma membrane with adapters that promote SHP2 activity. Consistent with this, SHP2 immunoprecipitated from cells with EGFR mutation was active, and EGF treatment did not change this activity. Overall, our data suggest that a fraction of SHP2 is sequestered at the plasma membrane in cells with EGFR mutation in a way that impedes SHP2's ability to promote ERK activity and identify SHP2 as a potential target for co-inhibition with EGFR in NSCLC.

Dataset Information

Transcriptional profiling of non-small cell lung cancer cells with activating EGFR somatic mutations.

Background

Methodology/principal findings

Conclusions/significance

Publications

Transcriptional profiling of non-small cell lung cancer cells with activating EGFR somatic mutations.

Similar Datasets

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