Another step towards understanding drug-resistant cancers

The clue is in the chromosomes

The word ‘cancer’ describes a huge group of different diseases, each with its own challenges. And one of the biggest is the attempt to work out why certain drugs work for some patients and not others.

This week, a group of Cancer Research UK scientists have uncovered an important part of this puzzle. In research published in the journal Cancer Research, they’ve shown that bowel cancer cells with ‘unstable’ chromosomes are more resistant to chemotherapy than cancer cells with more normal DNA.

This research is a small step towards the ultimate goal of personalising cancer treatment, helping patients receive the drugs that will work best for them. But before we look to the future, let’s find out a bit more about the new study.

Unstable chromosomes and cancer

Dr Charles Swanton and his team at Cancer Research UK’s London Research Institute are studying a phenomenon known as chromosomal instability.

As the name suggests, chromosomal instability happens when the normal arrangement of chromosomes in a cell goes awry. Healthy human cells should have a full set of exactly 46 chromosomes – packages of DNA that make up the cell’s genetic code. But some cancer cells buck this trend, managing to survive with too many or too few chromosomes, or even chromosomes that are completely the wrong shape or size.

And once a cell’s chromosomes have started to become unstable, it increases the chances that even more will go wrong.

You can see how chromosomal instability happens in this short video.

Understanding chromosomal instability and cancer

It’s becoming clear that people whose cancers have unstable chromosomes tend to have a worse outcome than people whose tumours have more well-behaved chromosomes. Dr Swanton has already shown that ovarian cancers with such chromosomes tend to be more resistant to drugs called taxanes, and the latest study shows that unstable bowel cancer cells can also evade the effects of several drugs.

But there’s a silver lining to this ‘bad news’ – Dr Swanton has already found a way to analyse breast cancer cells with unstable chromosomes to predict which drugs will work against them. And more research into the phenomenon could help to personalise treatment for other types of cancer in the future.

Solving the puzzle of drug resistance

Dr Swanton’s latest study focuses on how chromosomal instability affects chemotherapy for bowel cancer.

His team tested a class of drugs called kinase inhibitors on cancer cells with unstable chromosomes and on those without. These drugs block molecular messages within cancer cells that tell them to divide.  The scientists discovered that cells with unstable chromosomes were much more resistant to the drugs than those with more normal chromosomes, in keeping with results from studies on other types of cancer cell.

But how does having unstable chromosomes help cancer cells survive?

The team carried out further experiments, which showed that cancer cells with unstable chromosomes weren’t growing any faster than cells with normal chromosomes. Nor did there seem to be any specific gene faults or extra chromosomes responsible for the cells’ invincibility. It appears that the key to drug resistance is simply for cancer cells to have any degree of chromosomal instability.

From cells to patients

Chromosomal instability clearly has an important effect on cancer cells in the lab. But does this translate to an effect on patients?

The team looked at the results from 30 studies of patients with bowel cancer, and found that people whose cancer cells had unstable chromosomes generally had worse outcomes. Their cancers tended to come back more quickly after treatment with chemotherapy, and they also did not survive for as long as patients whose tumours were more stable.

Unravelling the results

These results are intriguing but it’s still not clear exactly why bowel cancer cells with unstable chromosomes become resistant to drugs. Dr Swanton does however have some ideas.

One theory is that cancer cells with chromosomal instability are all slightly different from each other because of their continually changing chromosomes. Drug treatment can kill off some cells, but the concept of the ‘survival of the fittest’ still applies.  Cells with the ‘strongest’ assortment of chromosomes will survive and carry on growing, meaning drug treatment will be less effective.

There’s also another possibility. Cells with unstable chromosomes already need to be quite special to cope with their messed-up DNA – a normal cell with the wrong number of chromosomes simply can’t survive. Perhaps the genetic changes that give cancer cells this ‘superpower’ are also helping them to resist certain cancer drugs.

This second theory is thought to be most likely. For example, it’s possible that when a cell’s chromosomes first start to go awry, the signals that would normally tell it to self-destruct don’t work. This might allow the cell to carry on copying itself, building up more and more genetic changes that give the resulting cells more resistance against certain drugs.

How can we use this knowledge?

The phrase ‘knowledge is power’ is a very apt one in cancer research. We don’t yet know exactly how cancer cells with unstable chromosomes become resistant to drugs, or how to target them to treat bowel cancer. But the new findings from this study are still extremely useful.

Knowing that bowel cancers with unstable chromosomes won’t respond to certain drugs has big implications for clinical trials testing new ways to treat the disease. The researchers point out that it will be crucial to identify patients whose cancers show chromosomal instability at the start of trials, so that the results can be analysed with this in mind. Otherwise, results from patients with drug-resistant cancers could mistakenly suggest that certain drugs won’t work for anyone with bowel cancer.

Understanding that bowel cancers aren’t all the same and investigating the differences between them will take us one step closer to more personalised treatment for the disease. And back in the lab, researchers will continue to probe the inner workings of cancer cells and their chromosomes, to find clues for potentially life-saving treatments.

Nell Barrie, Senior Science Communications Officer

Reference:

Lee et al (2011). Chromosomal instability confers intrinsic multi-drug resistance. Cancer Research