Combined inhibition of PI3K and Src kinases demonstrates synergistic therapeutic efficacy in clear-cell renal carcinoma

Abstract

Potent inhibitors of PI3K (GDC-0941) and Src (Saracatinib) exhibit as individual agents, excellent oral anticancer activity in preclinical models and have entered phase II clinical trials in various cancers. We found that PI3K and Src kinases are dysregulated in clear cell renal carcinomas (ccRCCs), an aggressive disease without effective targeted therapies. In this study we addressed this challenge by testing GDC-0941 and Saracatinib as either single agents or in combination in ccRCC cell lines, as well as in mouse and PDX models. Our findings demonstrate that combined inhibition of PI3K and Src impedes cell growth and invasion and induces cell death of renal carcinoma cells providing preclinical evidence for a pairwise combination of these anticancer drugs as a rational strategy to improve renal cancer treatment.