Trk inhibitor GNF‑5837 suppresses the tumor growth, survival and migration of renal cell carcinoma

Abstract

The clinical treatment of renal cell carcinoma (RCC) remains a major challenge. A number of novel agents and therapeutic strategies are currently undergoing active investigation. In the present study, we investigated the potential of GNF-5837, a Trk inhibitor, in the treatment of RCC. Tropomyosin-related kinases (Trk), a family of neurotrophin receptors, are vital for neural development and have also been identified as prognostic markers in malignancies of diverse origins. In the present study, we demonstrated that GNF-5837, an inhibitor of TrkA and TrkB, suppressed the cell viability of renal carcinoma 786O and Caki-2 cells in a concentration-dependent manner. GNF-5837 treatment led to decreased activities of TrkA and TrkB signaling, accompanied by reduced phosphorylation levels of AKT and extracellular signal-regulated kinase (ERK) kinases, which was detected by western blot assay. GNF-5837 induced G0/G1-phase arrest and apoptosis. Consistently, GNF-5837 affected the expression of p21, c-Myc, and survivin proteins. Meanwhile, a wound healing assay showed that GNF-5837 inhibited the migration ability of RCC cells by impairing Rac1 activity. GNF-5837 also enhanced the cytotoxic effects of sunitinib via inhibition of ERK kinase. Taken together, these results identify the pharmacological potential of targeting Trk signaling as a therapeutic strategy for RCC.