Cancer Research UK scientists have discovered a key mechanism that protects lung cancer from the lethal effects of chemotherapy.
Professor Michael Seckl and his team in London are investigating small cell lung cancer (SCLC), a particularly fast growing form of the disease, which is difficult to treat.
Their study, published in Molecular and Cellular Biology1, has found cancer cells activate a two stage survival strategy when exposed to anti-cancer drugs – ensuring they are doubly protected against death.
Researchers believe understanding how lung cancer resists treatment will help in the design of new drugs to attack the disease.
All cells have a natural suicide mechanism, which is carefully controlled and set off when they are old or damaged. In cancer this self-destruct mechanism is faulty so cancer cells escape their fate and continue to survive.
A drug called etoposide can trigger cell death in SCLC and is used to treat the disease. But eventually cancer cells develop a resistance to the drug.
Prof Seckl, from the Cancer Research UK Lung Cancer Biology Group at Imperial College London, says: “Small cell lung cancer grows incredibly quickly and many patients are diagnosed with advanced disease. The disease is usually inoperable, so we treat patients with a combination of chemotherapy and radiotherapy.
“Initially conventional anti-cancer drugs can be effective but the disease often returns in a form which is very resistant to further treatment. It’s a huge stumbling block in the effective treatment of lung cancer. But by studying the molecular basis of this resistance we can find ways to block it and restore the disease’s sensitivity to existing treatments.”
Researchers found that a molecule called FGF-2 2 helps cancer cells to survive by shutting down their suicide mechanism.
FGF-2 does this by increasing the levels of molecules called IAP’s 3, which inhibit cell death. IAP’s stop the action of another molecule called caspase-9 that helps trigger a chain of events leading to cell suicide.
IAP’s also block the release of a molecule called Smac – which is needed to fully activate the cells self-destruct mechanism.
Prof Seckl says: “We knew FGF-2 was found in much higher levels in the blood of people with cancer. The cancer cells use this molecule to protect themselves from chemotherapy and ensure their survival.
“Our study has shown that FGF-2 works by restricting the cells central death machinery at two key points. By blocking its effects we can force cancer cells to commit suicide and restore their sensitivity to anti-cancer drugs.”
The team are now looking at drugs that can target IAP’s to see if they can reverse the resistance of SCLC to chemotherapy.
Professor Robert Souhami, Executive Director of Clinical, Corporate and External Affairs, says: “The major obstacle to treating small cell lung cancer is the resistance the disease develops to chemotherapy. Finding the molecular basis to this is vital in order to develop new drugs and improve survival for patients.”
- Molecular and Cellular Biology23 (21)
- FGF-2 = Fibroblast Growth Factor-2
- IAP = Inhibitor of Apoptosis Protein