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Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 2, pp 411–420 | Cite as

Reduced proliferation and colony formation of head and neck squamous cell carcinoma (HNSCC) after dual targeting of EGFR and hedgehog pathways

  • Hannes Liebig
  • Georg Günther
  • Marlen Kolb
  • Christian Mozet
  • Andreas Boehm
  • Andreas Dietz
  • Gunnar WichmannEmail author
Original Article

Abstract

Purpose

The hedgehog signalling pathway (Hh) is frequently active in head and neck squamous cell carcinoma (HNSCC). Overexpressed Hh associates with poor prognosis. The Hh inhibitor vismodegib targets smoothened, and based on molecular data, may prevent resistance to EGFR targeting.

Methods

To elucidate potential roles of vismodegib in HNSCC therapy, its sole effects and those combined with cisplatin, docetaxel, and cetuximab on HNSCC cell lines were assessed by MTT metabolisation and BrdU incorporation. Colony formation (CF) of primary HNSCC cells was studied utilizing the FLAVINO-protocol. Combinatory effects were analysed regarding antagonism, additivity or synergism. Associations between the ex vivo detected mode of action of vismodegib with other treatments related to patient characteristics were assessed and progression-free survival (PFS) in patient groups compared using Kaplan–Meier curves.

Results

Vismodegib suppressed BrdU incorporation significantly stronger than MTT turnover; CF was significantly inhibited at ≥20 µM vismodegib while concentrations <20 µM acted hormetic. Combining 20 µM vismodegib plus docetaxel (T), cisplatin (P), and cetuximab (E), additively enhanced anti-tumoral activity in HNSCC samples from patients with superior PFS highlighting a potential role for ex-vivo testing of this combination for use as a prognostic classifier.

Conclusion

We provide ex-vivo evidence for vismodegib’s potential in HNSCC therapies, especially if combined with cetuximab, cisplatin and docetaxel.

Keywords

Head and neck squamous cell carcinoma (HNSCC) Head and neck cancer (HNC) Vismodegib Erivedge® Hedgehog signalling pathway SMO 

Notes

Acknowledgements

We thank Anett Reiche for excellent technical assistance and the patients and their families for participation in the study.

Compliance with ethical standards

Funding

The study was supported by the Grant EPGZ268406-G from Roche Pharma AG.

Conflict of interest

Gunnar Wichmann received funding for a translational research project on “Efficacy of vismodegib (GDC-0449) on HNSCC ex vivo, EPGZ268406-G” from Roche Pharma AG. All other authors declare no conflict of interest.

Ethical approval

The study was performed in accordance with the ethical standards as laid down in the 1964 declaration of Helsinki and its later amendments (vote 201-10-12072010 of the local ethics committee at the Medical Faculty of the University Leipzig).

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Hannes Liebig
    • 1
  • Georg Günther
    • 1
  • Marlen Kolb
    • 1
  • Christian Mozet
    • 1
  • Andreas Boehm
    • 1
  • Andreas Dietz
    • 1
  • Gunnar Wichmann
    • 1
    Email author
  1. 1.ENT-Research Laboratory, Clinic for Otorhinolaryngology, Head and Neck SurgeryUniversity Hospital LeipzigLeipzigGermany

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