Glutaminase inhibition confers antitumor effects in vitro and in vivo on tyrosine kinase inhibitors-resistant renal cell carcinoma cells by affecting vascular endothelial growth factor signaling

Tyrosine kinase inhibitors (TKIs) are key drugs in advanced renal cell carcinoma. Their prolonged efficacy is expected to translate directly into improved prognosis for patients with advanced renal cell carcinoma. In our previous studies, we identified important metabolic pathways related to sunitinib resistance. In this study, we examined whether TKI resistance could be overcome by controlling the glutamine metabolic pathway involved in sunitinib resistance. We established multiple renal cancer cell lines resistant to sunitinib and cabozantinib. We analyzed changes in the glutamine metabolic pathway associated with drug resistance. Furthermore, we inhibited the glutamine metabolic pathway using a glutaminase inhibitor (GLSi) and examined the antitumor effects of these TKIs on resistant renal cancer cells in vitro and in vivo. We also analyzed the mechanism of the antitumor effect of GLSi. In all established TKI-resistant cell lines, TKI resistance was associated with increased glutamine metabolism. GLSi showed significant antitumor effects on proliferation, invasion, and migration in all resistant cell lines. Immunostaining of resected TKI-resistant tumors demonstrated that GLSi-resistant TKIs exhibited sufficient antiangiogenic effects. VEGFR signal analysis suggested that the reduction of glutamate by GLSi activated PETN, which reduced VEGFR expression and its signaling, resulting in antitumor effects. GLSi has the potential to resensitize TKIs in TKI-resistant renal cancer cells. Therefore, controlling glutamine metabolism may extend the efficacy of existing TKIs and further improve the prognosis of patients with advanced renal cancer.