Prognostic factors of the therapeutic efficacy of mTOR and VEGFR inhibitors in patients with metastatic renal cell carcinoma

Abstract

Background. Thorough study of the molecular genetic alterations in patients with hereditary and sporadic renal cell carcinoma (RCC) enabled to reveal potential therapeutic targets - vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), growth factor receptors (VEGFR, PDGFR, EGFR, FGFR), mTOR signaling protein. Advances in targeted therapy treatment in the current therapeutic practice have brought a problem of its rational use and ultimately effective outcomes. The main solution of solving this problem is to establish independent clinical and laboratory prognostic factors and molecular markers which could predict the efficacy of targeted therapy. Objective – optimization of targeted therapy in patients with RCC by using both molecular and genetic prognostic factors as predictors of the treatment efficacy. Materials and methods. We assessed the level of mRNA expression of 13 potential target genes in primary tumor and metastatic site of patients suffering from metastatic RCC (n = 43) and evaluated the influence of the selected genes’ expression on the therapeutic efficacy of mTOR inhibitors and VEGFR inhibitors. Conclusion. VEGFR1 mRNA overexpression in metastatic site as well as mTOR and/or PI3K mRNA overexpression could be assessed as potential biomarkers in predicting the treatment efficacy of VEGFR inhibitors and mTOR inhibitors respectively. The higher expression of RAF1 mRNA and mTOR signaling pathway are not typical molecular alterations in patients with mRCC. RAF1 mRNA overexpression in metastatic site as well as activation of the alternative signaling pathway (RAS-RAF-MAPK) in tumor cell are negative prognostic factors of the efficacy of targeted therapy. Activation of the signaling RAS-RAF-MAPK pathway in tumor cells is probably an alternative independent mechanism that “drives” tumor development in certain groups of patients.