Abstract
Modifications of molecular features by the action of tyrosine kinase inhibitors (TKIs) in tumors are the basis of anticancer treatment efficacy. The aim of the study is investigation of AKT-m-TOR pathway components in kidney cancer tissues before and after TKI-targeted therapy. The study included 30 patients with metastatic clear cell kidney cancers. The treatment of these men consisted of pre-operational sorafinib targeted therapy in dose of 400 mg every day during the two months. Then the radical nephrectomy was performed. Content of phospho-PTEN, AKT (pan), phospho-AKT (T308), phospho-AKT (S473), phospho-GSK-3-beta (Ser9), phospho-PDK1 (Ser241), phospho-c-Raf (Ser259), m-TOR, phospho-mTOR (Ser2448), phospho-p70 S6 (Ser371), phospho-p70 S6 (T389) phospho-4E-BP1 (Thr37/46) was determined by western blotting analysis in tissues before and after targeted therapy. We have revealed the increased content of total AKT (pan), phospho-GSK-3-beta, phospho-PDK1, phospho-c-Raf in 91.0; 67.4; 46.0% and 69.0% in cancer tissues, respectively, compared with unaltered ones. The m-TOR, its phosphorylated form and phospho-4E-BP1 in kidney cancers were increased 76.1%; 67.2% and 78.7%, respectively, in comparison to normal tissues. We found the reduced level of phospho-PTEN in 1.7 fold after treatment. It was also noted that the decrease in the amount of phosphorylated AKT (T308) was 1.5-fold compared with that before the treatment. The phospho-p70 S6 (S371) kinase expression was increased 1.9-fold in patients receiving TKI-targeted therapies. TKI-targeted therapy was associated with the reduction of AKT signaling pathway activation. The fall of PTEN and gain of p70 S6 kinase levels during treatment were observed Acknowledgments.
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