Antitumor effects of CEP32496 on urothelial carcinoma with BRAF mutation (V595E) in dogs.

Canine urothelial carcinoma (UC) has a BRAF gene mutation (V595E) with a high prevalence rate (67 to 87%). CEP32496 is a novel and highly potent BRAF inhibitor. As described in the literature, the efficacy of BRAF inhibitors, including CEP32496, for UC with V595E is limited. The objective of this study was to evaluate the effects of CEP32496 alone and in combination with other BRAF inhibitors on the cell viability and tumor growth of 5 UC cell lines with V595E. For reference, 7 BRAF inhibitors, including GDC0879, PLX4720, encorafenib, vemurafenib, dabrafenib, AZ628, and RAF265, were also evaluated. The results revealed that CEP32496 had a sensitive half-maximal inhibitory concentration (IC50) ranging from 16 nM to 150 nM. In addition, the combination of CEP32496 and vemurafenib resulted in lower IC50s than those of individual treatment. The synergism of CEP32496 with vemurafenib may be due to the different mechanisms of cell proliferation between the 2 inhibitors. In the xenograft model, 10 mg/kg body weight of CEP32496 resulted in a significant decrease (P < 0.05) in tumor growth in mice, with severe and extensive necrosis on histopathological examination. These results suggested that CEP32496 exerts antitumor effects on both cell proliferation and tumor growth in UC with V595E.