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

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Item Type:Review
Title:Activation of AMP-activated protein kinase sensitizes lung cancer cells and H1299 xenografts to erlotinib
Creators Name:Huelsmann, H.J. and Rolff, J. and Bender, C. and Jarahian, M. and Korf, U. and Herwig, R. and Froehlich, H. and Thomas, M. and Merk, J. and Fichtner, I. and Sueltmann, H. and Kuner, R.
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.
Keywords:EGFR, AMPK, Erlotinib, Lung Cancer, Xenograft Models
Source:Lung Cancer
ISSN:0169-5002
Publisher:Elsevier (Ireland)
Volume:86
Number:2
Page Range:151-157
Date:November 2014
Official Publication:https://doi.org/10.1016/j.lungcan.2014.09.001
PubMed:View item in PubMed

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