New hope for ways to overcome drug resistance in lung cancer

Jul 13 2006

Scientists have suggested it may be possible to reverse drug resistance in lung cancer patients, thereby improving the effectiveness of chemotherapy, according to research published in the EMBO Journal.

Most lung cancer deaths are the result of tumours becoming drug resistant, which blocks the cancer-killing effects of chemotherapy. Now Cancer Research UK scientists have discovered the molecular basis of how a type of cancer called small cell lung cancer becomes resistant to treatment. They have identified a number of key proteins in the process that might also promote drug resistance in other forms of cancer.

The research raises the prospect of developing drugs to counteract this type of drug resistance and enable existing chemotherapy to successfully treat more lung cancer patients.

Lung cancer is the most common cancer in the world today and it accounts for more cancer deaths in the UK than any other form of cancer. About 20 per cent of lung cancers are small cell lung cancers. Most small cell lung cancer patients can only be treated with chemotherapy because most are undetected until the disease is at an advanced stage when it is too late for surgery.

Tumours with a protein called FGF-2 are known to be less likely to respond to treatment. The research team, led by Professor Michael Seckl and Dr Julian Downward, found that this is because FGF-2 is involved in the development of resistance to chemotherapy drugs.

Prof Seckl, of Cancer Research UK's Lung Cancer Biology Group at Imperial College London, said: "The main reason people die of lung cancer is drug resistance. We need to understand the precise mechanisms behind it or we will not be able to beat the disease."

Dr Downward, head of Cancer Research UK's Signal Transduction laboratory, said: "Looking at FGF-2 led us to other molecules required for drug resistance, particularly one called S6K2. We knew that S6K2 existed but no one knew exactly what it did before now. It seems to regulate a number of proteins that control whether cells live or die. It is also essential for the development of drug resistance in small cell lung cancer."

The researchers found that higher levels of S6K2 in both small cell and non small cell lung cancer tissue samples correlated with the development of drug resistance. They also found that patients who had relapsed after treatment had higher levels of S6K2 in their tumours. This suggested that chemotherapy initially killed lots of cancer cells, but cells with S6K2 were able to survive and pass on their resistance. New cancer cells therefore also had increased levels of S6K2 and the tumour became increasingly resistant to treatment.

Prof Seckl added: "There are already drugs in development that can block the action of FGF-2, but because it has important functions in healthy cells as well as generating drug resistance in cancer cells, blocking FGF-2 might have severe side effects in patients. S6K2 has fewer functions in healthy cells, so if we can develop new drugs that stop it working, it may be a better way to reverse drug resistance."

Professor John Toy, Cancer Research UK's medical director, said: "This research increases our understanding of how some lung cancer cells survive chemotherapy. If this kind of drug resistance could be overcome, it would be a major step forward in the treatment of lung cancer, which has proved so difficult to beat with existing chemotherapy drugs."