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| 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
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| 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.
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| 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.
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| Contributor(s) |
Greve G, Schiffmann I, Pfeifer D, Pantic M, Schüler J, Lübbert M |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Dec 02, 2014 |
| Last update date |
Nov 27, 2018 |
| Contact name |
Gabriele Greve |
| E-mail(s) |
gabriele.greve@uniklinik-freiburg.de
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| Organization name |
University of Freiburg Medical Center
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| Department |
Department of Internal Medicine 1
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| Lab |
Division of Hematology, Oncology and SCT, Lab Prof. Michael Lübbert
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| Street address |
Hugstetter Str 55
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| City |
Freiburg |
| ZIP/Postal code |
79106 |
| Country |
Germany |
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| Platforms (1) |
| GPL6801 |
[GenomeWideSNP_6] Affymetrix Genome-Wide Human SNP 6.0 Array |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA269073 |
| 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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