Future Horizons in Lung Cancer
Metabolomics: Reversing drug resistance
Dr Olivier Pardo - Imperial College London, London, UK
What I’ve talked about in this meeting was some of the latest data that we had in my lab which just has been accepted for publication in Cell Discovery that was about metabolomic analysis as a new way to find pathways that can be targeted in cancer to reverse drug resistance. In particular here we talked about resistance to EGFR targeted therapy and the way that our results from the metabolomics could inform how we could reverse that resistance.
What is metabolomic analysis?
Metabolomic analysis is looking at small molecule metabolites that are produced in the cells as part of cell metabolism and what you’re doing is you try to correlate changes in the level of these metabolites with changes in the overall behaviour of the cell. It has been known for quite a while now that cancer is associated with large-scale changes in the way cell metabolism happens. Changes in glycolytic pathway have been known for a very, very long time as part of the Warburg effect but now we’re coming to understand that this is only the tip of the iceberg and there are many more pathways that are being rewired or used differently in cancer cells versus normal cells and that are associated with tumorigenesis.
What pathways are you currently looking at?
We’ve been doing work in collaboration with the Chinese Academy of Science in Wuhan in China whereby we compared cells, lung cancer cells, that were resistant to EGFR targeted therapy with cells that were sensitive. In particular we used the background that is representing about 50% of the development of resistance to first generation inhibitors of EGFR which is a substitution that is a T790N mutation on the EGFR. What we have been showing is that occurrence of this mutation is associated with a decrease in the production of glutathione in the cancer cell and although we don’t understand yet how glutathione regulates that resistance what we can see is that the occurrence of this mutation changes the transcription of the enzymes that metabolise GSH leading to a lower production of GSH. If we modulate then this production, if we artificially, through for instance drug treatment, increase the level of GSH in the tumour we resensitise resistant tumours to erlotinib. That’s quite important because nowadays patients that are resistant to the first generation inhibitors like erlotinib due to the T790N mutation are put on third generation inhibitors that are extremely expensive, so this is a huge financial burden for health authorities, while here what we propose is that when the patient becomes resistant we could put the patient on a combination of still first generation very cheap inhibitors plus inhibitors of the degradation pathway of glutathione, resensitise these patients to first generation inhibitors and keep them longer on this treatment before they are required to go to more expensive novel drugs.
Would this save money?
It would save a large amount of money it could also, perhaps, delay the onset of resistance in the first place. So right now we’re looking at it as a way to reverse resistance but what we need to test is whether if you gave straight on the combination therapy with first generation EGFR inhibitor plus inhibitors of GSH degradation whether you could slow down the development of resistance in these patients and therefore maybe prevent it altogether.
What are your next steps?
Our next stage now is to go into patient-derived xenografts and trying to see whether we can reproduce in this setting what we see in animal models that we’ve used so far which were cell-based models. If we can, indeed, reproduce the difference that we see in vitro and in vivo in these animals in a patient-derived xenograft the next step is to go into clinical trial and we’ve got an inhibitor of GST that is ethacrynic acid, it’s a diuretic that has been used forever and a day, it’s now discontinued in Europe simply because it’s not a great diuretic but it’s non-toxic, it’s very, very cheap and what we show is that when we combine ethacrynic acid with erlotinib we resensitise resistant tumours. This is something that could go to the clinic tomorrow if you wish. Of course what we would be looking for in collaboration with the pharma company is seeing whether a specific GST inhibitor could be developed because ethacrynic acid targets GST as an off-target effect. But we believe that the results that we have could be even more profound if we had real GST inhibitors that would be much more efficient at inhibiting glutathione degradation.
