The effects of the inhibitors on pSTAT5 and pSTAT6 levels cisplatin dna were small, although as we demonstrated for other kinases, this does not necessarily reflect the activity of these kinases. Furthermore, leflunomide is not a very specific STAT6 inhibitor and we cannot exclude the possibility that the effect of leflunomide on cell sur vival is independent of Inhibitors,Modulators,Libraries STAT6 inhibition. The specificity of the used inhibitors might be con firmed by performing knockdown experiments with siRNAs against the kinases identified in these experi ments. However, also siRNAs are known to be prone to off target effects and transfection of cells can induce stress responses that could have important consequences for the response to radiation of these cells.

In addition, although specificity is an important issue, more import ant is that we show that multiple clinical available inhib itors have the potential to improve outcome after radiotherapy Inhibitors,Modulators,Libraries in HNSCC patients. Altogether, mostly additive effects of the kinase inhi bitors were observed Inhibitors,Modulators,Libraries in this study indicating that these inhibitors decreased tumor cell survival in general and not specifically after radiotherapy. Although a synergistic effect of a kinase inhibitor and radiotherapy would be preferred, combination therapies that result in reduced survival due to additive effects could still offer the prom ise of improving patient outcome after radiotherapy in the clinic. Especially when these additive effects occur in a large proportion of the patients.

Recurrences after radio therapy often occur from a few surviving clonogenic cells and this suggests that additional kill of clonogenic cells by a kinase inhibitor would contribute to local tumor control. Further research will be necessary to assess the effi cacy of these inhibitors Inhibitors,Modulators,Libraries to improve outcome after radio therapy in vivo and ultimately in patients. Some of the concentrations used in our experiments Inhibitors,Modulators,Libraries to inhibit kinases were in the micromolar range and it can be questioned whether effective inhibitor concentrations will be obtai nable in vivo and, hence, whether our findings can be directly extrapolated to the clinic. Our own group has already shown that combining dasatinib with radiotherapy results in a significant effect on growth delay in HNSCC xenografts, while either treatment alone has no effect on tumor growth.

In addition, clinical studies performed with dasatinib and MK 2206, have already shown to be selleck chem Enzastaurin able to effectively inhibit pSrc and pAKT, respectively. Nonetheless, it will still need to be determined whether these inhibitors are also able to improve outcome after radiotherapy in the clinic. Lastly, the challenge for the future will be to determine which kinase pathway are crucial for tumor cell survival in an individual patient and, hence, to determine which kinase inhibitor will most likely be effective in that patient.