Selectively targeting renal cell carcinoma by synthetic lethality

A major challenge in developing effective cancer therapies is targeting the tumour cells without harming the surrounding healthy tissue. A technique often used to identify such drugs is synthetic lethality. The basis of this technique is that the inhibition of a protein in a cell with an existing mutation leads to cell death, whereas inhibition of the same protein in healthy cells has little or no effect.

In a recent study by Chan et al. (2011), a high throughput chemical synthetic lethal screen was performed to identify compounds which selectively target RCC cells which have a VHL mutation. A total of 64,000 small molecules were screened using a fluorescence based cell assay. The STF-31 compound was identified as toxic for cells lacking VHL, but relatively nontoxic for cells with functional VHL.

STF-31 had no effect on autophagy, apoptosis or DNA damage in VHL-deficient cells, however it was shown to induce necrotic cell death. Further investigation found that STF-31 alters glycolysis by inhibiting glucose uptake. VHL-deficient cells rely on glycolysis for ATP production, a phenomenon known as the Warburg effect which has been discussed in a previous blog post. Targeting glycolysis allows healthy cells to use oxidative phosphorylation as an energy source, whilst inhibiting the ATP generation of cancerous cells. As expected, STF-31 was shown to cause a 75% decrease in ATP levels in VHL-deficient cells, whereas it had no effect on ATP levels in cells with functional VHL.

VHL-deficient cells have high levels of HIF activity, which results in increased expression of the glucose transporter GLUT1. Structural modelling predicted that STF-31 binds to GLUT1 at key residues important for its function, thereby inhibiting glucose uptake. This binding to GLUT1 was subsequently confirmed by affinity columns; however no binding to GLUT2, a second glucose transporter, was observed.

Interestingly, the authors found that other RCC cells lines that don’t have VHL mutations were also sensitive to STF-31. Sensitivity to the drug appears to be linked to the levels of GLUT1 and GLUT2 rather than to the functionality of the VHL protein. Cells with high GLUT1 and low GLUT2 expression levels were sensitive to STF-31.

Preston et al. (2010) showed that FLCN-null cells have high levels of GLUT1, due to increased HIF activity, and also exhibit the Warburg effect. It would be interesting to study the levels of GLUT2 in FLCN-null cells to see if STF-31 could be a potential therapy for BHD syndrome. STF-31 still requires further evaluation in vivo, but it is an exciting discovery in the development of treatments for RCC.

 

  • Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW, Banh A, Reynolds GE, Chi JT, Wu J, Solow-Cordero DE, Bonnet M, Flanagan JU, Bouley DM, Graves EE, Denny WA, Hay MP, Giaccia AJ. Targeting GLUT1 and the Warburg Effect in Renal Cell Carcinoma by Chemical Synthetic Lethality. Sci Transl Med. 2011 Aug 3;3(94). PMID:21813754
  • Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, Harper KT, Brinkhuizen T, Menko FH, Davies DM, Land SC, Pause A, Baar K, van Steensel MA, Tee AR. Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene. 2011 Mar 10;30(10):1159-73. PMID:21057536
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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