Chromosomal instability may predict resistance to cancer drug

Chromosomal instability may be linked to the resistance that some cancers have to certain anticancer therapies, according to research published in Cancer Cell* today (Monday). Identifying tumours without chromosomal instability might, therefore, help to target these therapies selectively to patients more likely to benefit.

Cancer Research UK scientists were looking for genes that influenced the response to paclitaxel (Taxol), a first-line treatment for breast cancer. They screened hundreds of key genes using RNA interference – a technique that uses small pieces of RNA**, each designed to block expression of a particular gene. By ‘switching off’ each gene in turn they were able to see what effect it had on drug resistance in various types of cancer cells.

The results suggest most of the genes that affected sensitivity to paclitaxel are among those known to play a role in maintaining the correct number of chromosomes in daughter cells after mitosis (cell division).

Doctors at Cancer Research UK and The Royal Marsden NHS Foundation Trust are now setting up a clinical trial to see whether they can use these findings to predict which patients will respond to paclitaxel or similar drugs.

If it works, a simple test could, in the future, help ensure patients receive the most effective available treatment for their cancer.

Paclitaxel belongs to a group of drugs called taxanes. They have been used in cancer chemotherapy for many years. They work by stopping cancer cells from completing the cell cycle, the process that leads to mitosis. This prevents cancer cells dividing and multiplying.

Normal human cells each have 23 pairs of chromosomes, which hold all of our genes. A key part of mitosis is making sure each of the two resulting daughter cells has the right number of correct chromosomes. A complex set of proteins controls this process – the so-called ‘spindle assembly checkpoint’. If these proteins don’t work properly, cells can end up with too many or too few chromosomes, a condition known as chromosomal instability, or CIN*** for short.

Many of the 25 genes which the screen found to be involved in paclitaxel resistance are associated with the spindle assembly checkpoint.

Dr Julian Downward, head of the Signal Transduction laboratory at Cancer Research UK’s London Research Institute, said: “Our findings are consistent with existing data that taxanes tend not to work so well in types of cancer where CIN is common. Colorectal cancer is a good example of this. Most colorectal cancers are resistant to taxanes, and we also know that a similar proportion of them exhibit CIN. While it hasn’t yet been proved that colorectal cancers with CIN are the same ones that don’t respond to taxanes, the proportional figures are suggestive.

“The results of our genomic screen support the theory that CIN is linked to resistance to taxanes. We’re now setting up a clinical trial, with the Royal Marsden Hospital gastrointestinal cancer unit, called CINATRA to test whether a taxane-like drug is indeed effective against those colorectal tumours that do not have CIN. Our hope is that a simple test for the presence of CIN will then be able to help target these drugs specifically to the patients who will benefit from them.”

Professor David Critchley, executive director of science at Cancer Research UK, said: “A lot of research is being done to develop new, highly-targeted therapies for cancer. However, this study shows we might also be able to find smarter ways to ‘target’ cancer treatments already in use.

“Taxanes are very useful anticancer treatments but are not used in bowel cancer because most tumours in the bowel don’t respond to them. But if we could find a reliable way to predict which tumours will respond to them, it might mean future patients, for whom these drugs would not currently be chosen, would perhaps have the opportunity to benefit from them.”

ENDS

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