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Background. Clear cell renal cell carcinoma (ccRCC) is the most frequent type of cancer in the kidney. These tumors are highly vascular and correlate with poor prognosis. Biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is a truncal event of ccRCC carcinogenesis, which yields new insights for targeted therapy. Our studies identified a small molecule, STF-62247, that is toxic to cells lacking VHL compared to RCC with a functional gene. We reported that STF-62247 blocks late stages of autophagy by targeting lysosome dynamics. Moreover, we identified lysosomal vulnerability in VHL-mutated ccRCCs, which could lead cells to death. Goal. This study aims to recognize and characterize STF-62247 potential targets. Results. Using biochemical approaches, our results indicated that STF-62247 cytotoxicity is driven by PIKfyve inhibition. Binding affinity between PIKfyve and STF-62247 is around 5 nM. Intracytoplasmic vacuoles and enlargement of endolysosomes were observed, which was prevented by adding exogenous PI(3,5)P2. Moreover, PIKfyve inhibitors such as apilimod, YM201636, Vacuolin-1, APY0201 sensitize ccRCC with a loss of VHL. Finally, genetic knockdown of PIKfyve was achieved by CRISPR/Cas9 leading VHL-inactivated cells to death. Conclusion. Altogether, our studies identified, for the first time, PIKfyve as potential target for kidney cancer cells with a loss of VHL. Citation Format: Nadia Bouhamdani, Sandra Turcotte. Identifying PIKfyve as potential target in clear cell renal cell carcinoma with a loss of the von Hippel-Lindau tumor suppressor gene. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3956. |
