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  Activation of AMP-activated protein kinase sensitizes lung cancer cells and H1299 xenografts to erlotinib

Hülsmann, H. J., Rolff, J., Bender, C., Jarahian, M., Korf, U., Herwig, R., et al. (2014). Activation of AMP-activated protein kinase sensitizes lung cancer cells and H1299 xenografts to erlotinib. Lung Cancer, 86(2), 151-157. doi:10.1016/j.lungcan.2014.09.001.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0026-B2C5-5 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0026-B2C6-3
Genre: Journal Article

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Hülsmann.pdf (Publisher version), 2MB
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2014
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© 2014 Elsevier B.V.
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 Creators:
Hülsmann, Helen J., Author
Rolff, Jana, Author
Bender, Christian, Author
Jarahian, Mostafa , Author
Korf, Ulrike, Author
Herwig, Ralf1, Author              
Fröhlich, Holger, Author
Thomas, Michael, Author
Merk, Johannes, Author
Fichtner, Iduna, Author
Sültmann, Holger, Author
Kuner, Ruprecht, Author
Affiliations:
1Bioinformatics (Ralf Herwig), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479648              

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Free keywords: EGFR; AMPK; Erlotinib; Lung cancer; Xenograft models
 Abstract: Objectives The therapeutic scheme for non-small cell lung cancer (NSCLC) patients can be improved if adapted to the individual response. For example, 60–70% of adenocarcinoma patients show response to EGFR-tyrosine kinase inhibitors in the presence of mutated EGFR. We searched for additional target molecules involved in the action of the EGFR-tyrosine kinase inhibitor erlotinib in the absence of EGFR mutations, which might be suitable for combinatorial therapy approaches. Materials and Methods Erlotinib-response associated proteins were investigated in patient-derived NSCLC mouse xenografts by reverse-phase protein array technology (RPPA) and Western blotting. A combinatorial treatment approach was carried out in NSCLC cell lines and H1299 mouse xenografts, and subsequently analyzed for consequences in cell growth and signal transduction. Results AMP-activated protein kinase (AMPK) expression was increased in erlotinib responders before and after treatment. In a combinatorial approach, activation of AMPK by A-769662 and erlotinib treatment showed a synergistic effect in cell growth reduction and apoptosis activation in H1299 cells compared to the single drugs. AMPK pathway analyses revealed an effective inhibition of mTOR signaling by drug combination. In H1299 xenografts, the tumor size was significantly decreased after combinatorial treatment. Conclusion Our results suggest that AMPK activation status affects response to erlotinib in distinct lung tumor models.

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Language(s): eng - English
 Dates: 2014-09-102014-11
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.lungcan.2014.09.001
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Title: Lung Cancer
Source Genre: Journal
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Publ. Info: Elsevier
Pages: - Volume / Issue: 86 (2) Sequence Number: - Start / End Page: 151 - 157 Identifier: -