In recent years, several approved small-molecule kinase inhibitors have been shown to prolong survival of patients with renal cell carcinoma (RCC), but there is still a major need for novel therapies. Turcotte and colleagues now present data indicating that the molecule STF-62247 — identified by screening RCC cells deficient in the von Hippel–Lindau (VHL) tumour suppressor gene, which is inactive in 75% of patients with RCC — induces cytotoxicity and reduces RCC growth through autophagy.

To identify STF-62247, the authors screened 64,000 compounds against wild-type VHL and VHL-deficient RCC cells. STF-62247 was shown to be selectively toxic to VHL-deficient cells compared with wild-type cells. Next, using VHL-null RCC4 cells expressing short-hairpin RNA against the VHL-regulated genes hypoxia-inducible factor 1α (HIF1α) and HIF2α, they showed that reduced expression of HIF1α or HIF2α did not affect cell death induced by STF-62247. Previously HIF2α has been shown to be crucial for tumour growth in RCC but this result indicated that cytotoxicity in VHL-null cells induced by STF-62247 is independent of HIF.

To test the effect of STF-62247 on tumour growth in vivo, VHL-deficient RCC tumours were implanted into immunodeficient mice. Daily treatment with STF-62247 induced a concentration-dependent decrease in VHL-deficient tumour growth but had no effect on wild-type VHL tumours.

In vitro studies investigating the mechanism of action showed that STF-62247 does not induce apoptosis or change the phosphorylation or total levels of p53 in VHL-deficient cells, suggesting that the molecule does not act via a DNA damage signalling pathway. However, the cells accumulated intracytoplasmic vacuoles characteristic of cells undergoing autophagy. This was confirmed by detecting the lipidated form of the microtubule-associated protein light chain 3 found in cells undergoing autophagy in an STF-66247 concentration-dependent manner.

Several studies indicated that STF-66247 targets the trans-Golgi network (TGN): brefeldin A, a blocker of protein transport from the endoplasmic reticulum to the Golgi apparatus, abolished the formation of autophagic vacuoles in STF-62247-treated VHL-deficient cells. Also, a screen of a yeast deletion pool showed that cells lacking proteins involved in Golgi trafficking and in morphogenesis were more sensitive to STF-62247. Moreover, small interfering RNA knockdown of three proteins involved in the trans-Golgi network — ALG5, OSBPL3 and CHMP6 — correlated with VHL status and increased vacuole formation in response to STF-62247.

Overall, STF-62247 induces autophagy — a process that has been implicated in a number of diseases including neuronal degeneration, infectious disease and cancer — in a HIF-independent manner by targeting the TGN, and presents a new opportunity for developing targeted treatments for VHL-deficient RCC.