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. 2017 Jun 7;12(6):e0178930.
doi: 10.1371/journal.pone.0178930. eCollection 2017.

Efficacy of targeted drugs in germ cell cancer cell lines with differential cisplatin sensitivity

Judith Schaffrath  1 , Hans-Joachim Schmoll  2 , Wieland Voigt  3 , Lutz P Müller  1 , Carsten Müller-Tidow  4 , Thomas Mueller  1
Affiliations

Efficacy of targeted drugs in germ cell cancer cell lines with differential cisplatin sensitivity

Judith Schaffrath et al. PLoS One. .

Abstract

Methods: The in vitro activity of kinase inhibitors targeting mTOR (RAD001), EGFR, HER2/neu, VEGFR (AEE788) and IGF-1R (AEW541) alone or in combination with cisplatin was tested in the cisplatin sensitive TGCT cell lines H12.1 and GCT72 as well as in the resistant cell lines H12.1RA, H12.1D, 1411HP and 1777NRpmet using the sulforhodamin-B-(SRB)-cytotoxicity-assay. To evaluate the activity of the kinase inhibitors, western blot analysis of the targeted receptors and their phosphorylated state was performed before and after exposure to each substance.

Results: The different kinase inhibitors demonstrated significant cell growth inhibition in both cisplatin sensitive and resistant cell lines. The examined cell lines showed different protein expression levels of the targeted receptors. However there was no correlation between the targeted receptor expression and phosphorylation level and the antiproliferative effect of the respective agent. Furthermore, the combination of cisplatin and the kinase inhibitors exerted both additive and antagonistic effects in the studied cell lines.

Conclusion: Our data suggest potential activity of the investigated kinase inhibitors in both cisplatin sensitive and resistant TGCT cell lines as a single agent. However, when combined with cisplatin they did not demonstrate any promising ability to overcome cisplatin resistance in TGCTs.

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Conflict of interest statement

Competing Interests: The study was financially supported by Novartis Pharma GmbH (www.novartis.com). This does not alter our adherence to PLOS ONE policies on sharing data and materials. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The author LPM got travel grants and honoraria for speaking or participation at meetings but not related to the subject matter of this manuscript. The authors have to declare no further competing interests related to the subject matter of this manuscript.

Figures

Fig 1
Fig 1. Dose-response curves of RAD001 in TGCT cell lines.
(96 h of exposure, n = 3, mean ± SD).
Fig 2
Fig 2. Dose-response curve of cisplatin compared to the combination of cisplatin and RAD001 in the cell line 1411HP.
(96 h of exposure, n = 3, mean ± SD).
Fig 3
Fig 3. Expression and phosphorylation of EGFR, HER2/neu, VEGFR, IGF-1R and mTOR in all cell lines.
Fig 4
Fig 4. Expression and phosphorylation of mTOR after treatment with AEE788 (IC30) and RAD001 (30 nM) over 24 h compared to untreated controls.
The additional band at P-mTOR S2481 (H12.1RA, 24 h) is caused by the marker.
See this image and copyright information in PMC

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