Targeted therapy for the loss of von Hippel-Lindau in renal cell carcinoma: A novel molecule that induces autophagic cell death

Radiation and conventional cytotoxic chemotherapies are ineffective in treating renal cancer. Approximately 75% of renal cell carcinoma (RCC) is associated with an inactivation of the tumor suppressor gene von Hippel-Lindau (VHL). We exploited the possibility of targeting VHL-deficient RCC through synthetic lethality using a high-throughput screening approach. In this screen, STF-62247 was identified to be selectively toxic and growth inhibitory to renal cells lacking VHL. We recently demonstrated that the cytotoxicity of STF-62247 is due to dysregulated autophagy. Furthermore, the reduction of protein levels of essential autophagy pathway components such as Atg5, Atg7 and Atg9 reduces sensitivity of VHL-deficient cells to killing by STF-62247. Loss of proteins involved in Golgi trafficking sensitized RCC with wild-type VHL to killing by STF-62247, indicating a potential role for these proteins as a target of the compound. Our study supports the concept of using synthetic lethality to selectively kill VHL-deficient cells that represents a new type of targeted therapy for the treatment of RCC. Addendum to: Turcotte S, Chan DA, Sutphin PD, Hay MP, Denny WA, Giaccia AJ. A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 2008; 14:90-102.