Effect of KO-2806 and cabozantinib treatment on gene expression in KI-12-0073 clear cell renal cell carcinoma (ccRCC) xenografts

Anti-angiogenic tyrosine kinase inhibitors (TKIs) 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. There is therefore a need for therapeutic agents that enhance responses to TKIs, including in patients who progress on prior TKI therapies. Here we show that the farnesyl transferase inhibitor (FTI) KO-2806 inhibits mTORC1 signaling in endothelial cells to enhance the antiangiogenic properties of TKIs. This activity correlates with tumor regressions and robust inhibition of tumor vasculature in preclinical models of clear cell RCC (ccRCC) exposed to the combination of anti-VEGFR TKIs and KO-2806. Additionally, the KO-2806 plus anti-VEGFR TKI combinations retain activity in tumors previously exposed to TKIs, suggesting potential benefit of KO-2806 as a combination partner across the treatment continuum in RCC.