161 AKT IS A POTENTIAL TARGET FOR OVERCOMING ACQUIRED RESISTANCE TO TYROSINE KINASE INHIBITORS IN RENAL CELL CARCINOMA

Abstract

INTRODUCTION AND OBJECTIVES: Sorafenib is one of multikinase inhibitors widely used in patients with advanced kidney cancer. It exerts its anti-tumor effect not only by inhibiting signal pathways in cancer cells but also by constraining myeloid-derived suppressor cells (MDSC). Recently novel antibody against CTLA-4 that activates lymphocyte has been developed and is now under clinical trials. The aim of this study is to investigate whether low-dose sorafenib could augment the anti-tumor effect of anti-CTLA4 antibody (CTLA-4 Ab) in the murine kidney cancer model. METHODS: RENCA cells were inoculated subcutaneously to BALB/c mice, and mice were randomly divided into 4 groups, including (1) low-dose sorafenib (10 mg/kg) plus CTLA-4 Ab, (2) low-dose sorafenib plus PBS, (3) vehicle plus CTLA-4 Ab, and (4) vehicle plus PBS. Sorafenib or vehicle control were administered orally once daily for 7 days to 21 days. CTLA-4 Ab was administered intraperitoneally at day 7, day 12 and day 17. The mice were sacrificed at day 21, then tumor infiltrating lymphocyte was analyzed by immunohistochemistry. RESULTS: All three treatment groups ((1), (2) and (3)) showed a statistically significant decrease in tumor size compared with vehicle plus PBS group. In particular, combination of low-dose sorafenib and CTLA-4 Ab exhibited the most significant anti-tumor effect. Increase in infiltrating CD4or CD8-positive lymphocyte was detected in CTLA-4 Ab alone group and low-dose sorafenib plus CTLA-4 Ab group. Especially, combination of low-dose sorafenib and CTLA-4 Ab demonstrated the most potent effect to trigger the infiltration of both CD4-positive lymphocyte and CD8-positive lymphocytes. These in vivo results indicate that sorafenib bolsters the immunostimulatory effect of CTLA-4 Ab even at the low dose. CONCLUSIONS: Combination therapy of low-dose sorafenib and anti-CTLA-4 antibody can be a potential therapeutic option for advanced kidney cancer patients.