Combining radiotherapy with MEK1-2, STAT5 or STAT6 inhibition reduces survival of head and neck cancer linesReportar como inadecuado

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Molecular Cancer

, 12:133

First Online: 05 November 2013Received: 10 July 2013Accepted: 31 October 2013DOI: 10.1186-1476-4598-12-133

Cite this article as: Stegeman, H., Kaanders, J.H., Verheijen, M.M. et al. Mol Cancer 2013 12: 133. doi:10.1186-1476-4598-12-133


BackgroundKinases downstream of growth factor receptors have been implicated in radioresistance and are, therefore, attractive targets to improve radiotherapy outcome in head and neck squamous cell carcinoma HNSCC patients.

MethodsAn antibody-based array was used to quantify the expression levels of multiple phospho-kinases involved in growth factor signaling in nine untreated or irradiated HNSCC lines. Radiosensitivity was assessed with clonogenic cell survival assays and correlated with the expression levels of the phospho-kinases. Inhibitors of the kinases that were associated with radiosensitivity were tested for their ability to increase radiosensitivity in the 3 most radioresistant HNSCC lines.

ResultsThe basal expression of phosphorylated Yes, Src and STAT5A, and the expression after radiotherapy of phosphorylated AKT, MSK1-2, Src, Lyn, Fyn, Hck, and STAT6, were correlated with radiosensitivity in the panel of HNSCC lines. In combination with radiotherapy, inhibitors of AKT, p38 and Src Family Kinases SFK were variably able to reduce survival, whereas MEK1-2, STAT5 and STAT6 inhibition reduced survival in all cell lines. The combined effect of radiotherapy and the kinase inhibitors on cell survival was mostly additive, although also supra-additive effects were observed for AKT, MEK1-2, p38 and STAT5 inhibition.

ConclusionsKinases of the AKT, MAPK, STAT and SFK pathways correlated with radiosensitivity in a panel of HNSCC lines. Particularly inhibitors against MEK1-2, STAT5 and STAT6 were able to decrease survival in combination with radiotherapy. Hence, inhibitors against these kinases have the potential to improve radiotherapy outcome in HNSCC patients and further research is warranted to confirm this in vivo.

KeywordsRadiation resistance Head and neck cancer Kinase inhibitors STAT5 STAT6 Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-12-133 contains supplementary material, which is available to authorized users.

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Autor: Hanneke Stegeman - Johannes HAM Kaanders - Marieke MG Verheijen - Wenny JM Peeters - Deric L Wheeler - Mari Iida - Reida


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