Wirkung des dualen PI3K/mTOR-Inhibitors NVP-BEZ235 auf die Kombination von Cisplatin und Bestrahlung bei HPV-negativen und -positiven Plattenepithelkarzinom-Zellen der Kopf-Hals-Region

Squamous cell carcinoma of the head and neck region (HNSCC) is the six most frequent malignant disease worldwide. Besides alcohol and nicotine consumption, local infection with human papilloma viruses (mainly HPV-16 and HPV-18) contributes to oncogenesis. Therefore, a distinction is made between HPV-neg. and HPV-pos. HNSCC. This tumour is generally treated by a multi-modal concept, which - especially in case of an advanced stage – includes radio-chemotherapy with cisplatin. While for HPV-neg. HNSCC 5-years survival is still below 50-60%, for HPV-pos. HNSCC values above 90% are reached. Unfortunately, these results are often accompanied with severe side-effects causing a drastic reduction in quality of life. It was shown in a previous report of this lab, that the PI3K/Akt/mTOR-pathway, which is often mutated in HNSCC, is strongly depressed, when using the specific inhibitor NVP-BEZ235 leading also to a pronounced radiosensitization, which is independent of the HPV status. It was now tested whether BEZ235 can also be used to enhance the effect of irradiation when combined with cisplatin. The experiments were carried in six HPV-neg. (FaDu, UM-SCC-3, UM-SCC-6, UM-SCC-11b, UT-SCC-33, Cal33) and six HPV-pos. lines (UD-SCC-2, UM-SCC-104, UM-SCC-47, 93VU-147T, UPCI:SCC-152, UPCI:SCC-154). This great number of cell lines was necessary to cover the broad heterogeneity of HNSCC cell lines. The effect on cell survival was determined via colony-forming-assay. Overall, the following results are obtained: 1. There was a trend that the effect of cisplatin alone on cell survival was stronger for HPV-pos. cells. 2. Pretreatment by 50 nM BEZ235 for two hours strongly enhances the effect of cisplatin in all six HPV-pos. cell lines, while except for UM-SCC-11b cells no such effect is seen for HPV-neg lines. 3. In line with previous data cisplatin alone was found to have no or only a marginal effect on radiosensitivity. For UD-SCC-2 cells even a slight reduction in radiosensitivity was observed. 4. In contrast, for all cell lines tested pretreatment of BEZ235 was found to result in a strong radiosensitization as already reported previously. 5. Pretreatment with BEZ235 was also found to enhance the effect of cisplatin on radiosensitivity. Even for a small X-ray dose of 2 Gy cisplatin was found to result in a significant radiosensitization, when cells were pretreated by BEZ235. It is shown for the first time for HNSCC-cells, that the suppression of the PI3K/Akt/mTOR-pathway by BEZ235 always results in significant enhancement of the combined treatment with X-irradiation and cisplatin. This effect was independent of the HPV status. Without pretreatment by BEZ235 cisplatin has no or only a minor effect on radiosensitivity. It needs to be investigated for HNSCC patients, whether such a pretreatment with BEZ235 can be used to enhance the effect of radiochemotherapy with cisplatin and thereby increasing the cure rate with a possible chance to reduce the side-effects for these patients.