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Series GSE63784 Query DataSets for GSE63784
Status Public on Dec 03, 2014
Title The HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR mutated and wildtype NSCLC cells
Organism Homo sapiens
Experiment type Genome variation profiling by SNP array
Summary Background: The receptor tyrosine kinase (RTK) EGFR is overexpressed and mutated in NSCLC. These mutations can be targeted by RTK inhibitors (TKIs) such as erlotinib. Chromatin-modifying agents may offer a novel therapeutic approach by sensitizing tumor cells to TKIs.
Methods: The NSCLC cell lines HCC827 (EGFR mutant, adenocarcinoma), A549 (EGFR wt, adenocarcinoma) andNCI-H460 (EGFR wt, large cell carcinoma) were analyzed by SNP6.0 array. Changes in proliferation after panobinostat (LBH-589, PS) and erlotinib treatment were quantified by WST-1 assay and apoptosis by Annexin V/7-AAD flow cytometry. Abundance of target proteins and histone marks (acH3, H3K4me1/2/3) was determined by immunoblotting.
Results: As expected, the EGFR wt cell lines A549 and NCI-H460 were quite insensitive to the growth-inhibitory effect of single-agent erlotinib (IC50 70-100 μM), compared to HCC827 (IC50 < 0.02 μM). PS treatment diminished growth to <50 % in both EGFR wt cells, and <30 % in HCC827. The combination of both drugs reduced proliferation by >95 % in HCC827, ≥70 % in A549, but not further in NCI-H460. PS alone induced differentiation and expression of p21WAF1/CIP1 and p53 and decreased CHK1 in all three cell lines, with almost no further effect when combined with erlotinib. In contrast, combination treatment additively decreased pEGFR, pERK, pAKT in A549, and synergistically induced acH3 in both adenocarcinoma lines. Surprisingly, we saw an induction of H3K4 methylation marks after erlotinib treatment in HCC827 (and to a lesser extent in A549) that was even further enhanced by combination with PS.
Conclusion: We were able to show that PS synergistically sensitized lung adenocarcinoma cells to the antiproliferative effects of erlotinib. Since single-agent erlotinib has only modest clinical effects in lung adenocarcinoma EGFR wt patients, its combination with an HDACi might offer a promising therapy approach.

Overall design Copy-number analysis of three NSCLC cell lines HCC827, A549 and NCI-H460 (in unicates) was performed according to protocol by Affymetrix Genome-Wide Human SNP-Array 6.0.
Contributor(s) Greve G, Schiffmann I, Pfeifer D, Pantic M, Schüler J, Lübbert M
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Submission date Dec 02, 2014
Last update date Nov 27, 2018
Contact name Gabriele Greve
Organization name University of Freiburg Medical Center
Department Department of Internal Medicine 1
Lab Division of Hematology, Oncology and SCT, Lab Prof. Michael Lübbert
Street address Hugstetter Str 55
City Freiburg
ZIP/Postal code 79106
Country Germany
Platforms (1)
GPL6801 [GenomeWideSNP_6] Affymetrix Genome-Wide Human SNP 6.0 Array
Samples (3)
GSM1557132 NSCLC_cell line_genomic DNA_HCC827
GSM1557133 NSCLC_cell line_genomic DNA_A549
GSM1557134 NSCLC_cell line_genomic DNA_H460
BioProject PRJNA269073

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE63784_RAW.tar 189.9 Mb (http)(custom) TAR (of CEL, CNCHP, CN_SEGMENTS, TXT)
Processed data included within Sample table
Processed data provided as supplementary file

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