Farnesyl Transferase Inhibitor KO-2806 (Darlifarnib) Enhances the Antitumor Activity of Tyrosine Kinase Inhibitors in RCC.

Antiangiogenic tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) remain the backbone of therapy in advanced renal cell carcinoma (RCC). However, durability of responses is limited and resistance typically arises. Thus, there is an urgent need for therapeutic agents that enhance responses to TKIs, including in patients who progress on prior TKI therapies. In this study, we show that the farnesyl transferase inhibitor (FTI) KO-2806 inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling in endothelial cells to enhance the antiangiogenic properties of TKIs. This translates to tumor regressions and robust inhibition of tumor neovascularization in preclinical models of RCC exposed to the combination of KO-2806 and anti-VEGFR TKIs. KO-2806 also sensitizes tumors previously progressing on anti-VEGFR TKIs, suggesting potential benefits of KO-2806 as a combination partner across the treatment continuum in RCC.