Metabolism ‘rewiring’ leads to aggressive lung cancers

Scientists have discovered that lung cancers with extra copies of a cancer causing gene-defect ‘rewire’ their energy supply, helping them to survive and making them more likely to spread.

Researchers at the Medical Research Council (MRC) Cancer Unit at the University of Cambridge studied lung cancers with mutations in their Kras genes, which are found in around 30 per cent of adenocarcinomas – the most common type of primary lung cancer. They found that the number of copies of Kras mutations had a profound impact on the disease, as those with extra copies undergo a change in their metabolism.

Lung cancer cells with extra copies of Kras mutations increase their uptake of glucose – the major energy source in the body – and show alterations in the way this sugar is processed. Changes in glucose metabolism are a well-known cancer trait but this study revealed that cells with extra copies of mutant Kras utilise glucose differently from those either with a single mutation or normal lungs.

This metabolic “rewiring” enables these cells to cope better with certain cellular stresses but also means that they have unique metabolic needs that can be exploited therapeutically. Since an increase in the number of copies of Kras mutations were associated with more aggressive tumour features, such as the ability to spread, the therapeutic implications of the study are particularly appealing.

Until now all lung cancers with faulty Kras genes have been seen as one form of the disease. Dr Carla Martins, the lead researcher based at the MRC Cancer Unit, said: “Our study shows that we have been wrong to view all lung cancers with Kras faults as one form of lung cancer. Recognising that they may comprise distinct disease groups can help us improve the way we diagnose and treat these cancers.

“This is something urgently needed for patients with this type of the disease as current treatments have limited success. We now need to build on this work by determining the prevalence of this metabolic rewiring in patients and find ways to exploit or prevent it.”

The study is published in Nature.

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