Members of the STAT family have been shown to be activated in epithelial tumors, including HNSCC, and are known to induce the transcription Olaparib clinical trial of genes involved in cell survival, proliferation and angiogenesis. Acti vation of STAT5 has also been shown to contribute to tumor growth and resistance to cisplatin and EGFR inhibition in HNSCC cell lines. However, it has not been previously described that STAT5 and STAT6 cor relate with radiosensitivity as we find in our study. An other member of the STAT family, STAT3, has been shown to be involved in resistance to radiotherapy. Hence, our results indicate that also other STAT members play an important role in radiosensitivity in HNSCC. This is also indicated by a study of Lesterhuis et al, who observed a trend toward a shorter pro gression free survival for STAT6 expressing tumors in a cohort of HNSCC patients treated with radiotherapy only.
More importantly, inhibition of STAT5 and STAT6 consistently decreased survival after radiation in all cell lines. Although these effects on survival were mostly additive, these data do suggest that Inhibitors,Modulators,Libraries inhibition of STAT5 and STAT6 has the potential to improve outcome after radiotherapy in a large proportion of HNSCC patients. However, Inhibitors,Modulators,Libraries our results have to be interpreted with caution. The effects of the inhibitors on pSTAT5 and pSTAT6 levels 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 Inhibitors,Modulators,Libraries of 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 Inhibitors,Modulators,Libraries 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 in HNSCC patients. Inhibitors,Modulators,Libraries Altogether, mostly additive effects of the kinase inhi bitors were observed in this study indicating that these inhibitors decreased tumor cell survival in general and not specifically after radiotherapy. Although a synergistic effect selleck chem Volasertib 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.
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