Unstable chromosomes cause resistance to cancer drugs

Cancer Research UK scientists have made an important step towards developing personalised bowel cancer treatment by identifying which tumours are more likely to become drug resistant, according to research published in Cancer Research today.

The team at Cancer Research UK’s London Research Institute treated two classes of bowel cancer cells grown in the lab with around 250 compounds. These included common chemotherapy drugs used in bowel cancer and newer ‘targeted’ drugs which block specific faults in cancer cells.

The scientists tested one group of chromosomally unstable (CIN) bowel cancer cells, produced when faults in cell division can create more – or less – than the standard 46 chromosomes in daughter cells. Cells in the other group had a stable set of 46 chromosomes.

The team found that chromosomally unstable bowel cancer cells are significantly more resistant to a large number of chemotherapy treatments and targeted drugs, than cells with a stable chromosome number. And tumours with stable chromosomes are more likely to respond to drugs.

These results mean that determining the CIN status of tumours may provide useful information on whether bowel cancer patients will benefit from certain treatments. CIN tumours are the most aggressive, accounting for 70 per cent of all bowel cancer cases.

Lead author, Dr Charles Swanton, head of translational cancer therapeutics at Cancer Research UK’s London Research Institute, said: “One of the most important questions in cancer medicine is to find out why drugs work better in some patients than others – so doctors can prescribe the most beneficial treatments.

“Patients with cancers that have unstable chromosomes have a worse outlook and we suggest one reason for this may be their drug resistant nature. We’ve found that common cancer drugs may be more effective in tumours with a normal chromosome number than those with a chaotic, constantly changing chromosome content. We’re now trying to understand why this happens and how to prevent drug resistance in these cells.”

“Treating patients based on whether or not their cancers are chromosomally unstable would be a step towards the personalised management of the disease, which may one day help to improve survival for this most aggressive subtype of bowel cancer.”

At least 40 drugs, including the chemotherapy family of drugs to which Fluorouracil – also called FU or 5-FU – belongs, were shown to be more likely to kill bowel cancer cells containing stable chromosomes than their chromosomally unstable counterparts. None of the drugs were more effective in chromosomally unstable bowel cancer cells.

The team then searched through published clinical trial data, which confirmed the laboratory results. The data showed that patients with chromosomally stable bowel cancers showed significant improvement in survival when treated with Fluorourcil-based chemotherapy. But, patients with cancers with unstable chromosomes had a reduced chance of disease free survival after chemotherapy.

Dr Lesley Walker, Cancer Research UK’s director of cancer information, said:

“We’re making excellent progress in the treatment of bowel cancer. People diagnosed today are twice as likely to survive for at least ten years than those in the 1970s and our work has played a significant part in this progress.

“Developing treatments according to the genetic profile of patients is the next big focus – as not all bowel cancers are the same. These findings will help us unravel the underlying disease causes to tailor treatment to different groups of patients and find better drugs for advanced disease. The next stage will be to confirm this early research with larger studies.”

ENDS

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