Antitumor Effect of Cabozantinib in Bone Metastatic Models of Renal Cell Carcinoma

SIMPLE SUMMARY: Bone metastasis is a common and devastating feature of advanced renal cancer. Skeletal metastases are very destructive in patients with renal cell carcinoma (RCC), compromising the bone integrity and leading to fractures, pain, nerve compressions and hypercalcemia, with a negative impact on patient survival. Cabozantinib is a receptor tyrosine kinase inhibitor approved for the treatment of advanced RCC patients. Recently, preclinical studies demonstrated that cabozantinib is able to also modulate bone cell activity. To understand whether and how the antitumor activity of cabozantinib could be influenced by the bone microenvironment, in vitro co-culture models of renal cancer cells and osteoblasts (OBs) were developed to reproduce the bidirectional interplay between tumor cells and bone. The data showed that cabozantinib preserves its efficacy in these coculture models and exerts an additional indirect antitumor activity mediated by OBs. Indeed, cabozantinib is able to inhibit specific OB proliferative signals that, in turn, could affect RCC cell growth. To elucidate how OBs stimulate RCC cell growth could be useful in designing novel and more effective anticancer strategies to improve the efficacy of the existing treatments. ABSTRACT: Background: The presence of bone metastases in renal cell carcinoma (RCC) negatively affects patients’ survival. Data from clinical trials has highlighted a significant benefit of cabozantinib in bone metastatic RCC patients. Here, we evaluated the antitumor effect of cabozantinib in coculture models of renal cell carcinoma (RCC) and osteoblasts (OBs) to investigate whether and how its antiproliferative activity is influenced by OBs. Methods: Bone/RCC models were generated, coculturing green fluorescent protein (GFP)-tagged Caki-1 and 786-O cells with human primary OBs in a “cell–cell contact” system. RCC proliferation and the OB molecular profile were evaluated after the cabozantinib treatment. Results: The Caki-1 cell proliferation increased in the presence of OBs (p < 0.0001), while the 786-O cell growth did not change in the coculture with the OBs. The cabozantinib treatment reduced the proliferation of both the Caki-1 (p < 0.0001) and 786-O (p = 0.03) cells cocultured with OBs. Intriguingly, the inhibitory potency of cabozantinib was higher when Caki-1 cells grew in presence of OBs compared to a monoculture (p < 0.001), and this was similar in 786-O cells alone or cocultured with OBs. Moreover, the OB pretreatment with cabozantinib “indirectly” inhibited Caki-1 cell proliferation (p = 0.040) without affecting 786-O cell growth. Finally, we found that cabozantinib was able to modulate the OB gene and molecular profile inhibiting specific proliferative signals that, in turn, could affect RCC cell growth. Conclusions: Overall, the “direct” effect of cabozantinib on OBs “indirectly” increased its antitumor activity in metastatic RCC Caki-1 cells but not in the primary 786-O model.