Everolimus ve ABT-737' nin renal hücreli karsinom üzerindeki kemoterapötik etkisi

2-3 per cent of all malignant tumors are characterized as renal cell carcinoma (RCC), that shows a high mortality rate. Among a number of histopathological subtypes, clear cell RCC (ccRCC) comprises the majority and 20-30 per cent of patients diagnosed with ccRCC are already at locally advanced or metastatic stage. As the elevated activity of mTOR pathway is associated with RCC tumorigenesis, the mTOR kinase inhibitor, everolimus, is used in clinic for the cure of patients with metastatic RCC (mRCC). However, the low rate of progression free survival and the development of everolimus resistance are the main clinical limitations observed with everolimus therapy. Given the possible contribution of anti-apoptotic Bcl-2 protein in RCC development, everolimus was combined with a Bcl-2 protein inhibitor ABT-737 to overcome the everolimus resistance. The effect of everolimus combination with ABT-737 was studied in Bcl-2 overexpressing RCC cell lines, A-498 and Caki-1, and in RCC xenograft mouse model. The in vitro results indicated that the everolimus-ABT-737 combination led to a significant decrease in the both RCC cell lines' viability, which is associated with the attenuated cell cycle as a result of completely suppressed mTOR pathway as well as with the induction of apoptosis. Diminished level of anti-apoptotic Bcl-2 protein was also detected in A-498 and Caki-1 as a response to ABT-737 monotherapy and its combination with everolimus. In support of in vitro findings, the synergistic anti-tumor effect of everolimus-ABT-737 combination was validated in RCC xenograft Balb/c mouse model generated with the RenCares cell line. Taken together, the findings from this thesis suggest that the everolimus-ABT-737 combination as a novel therapy strategy can provide therapeutic benefit for the patients suffering from the advanced RCC. This study was supported by TUBITAK (114S332)