As they go about their daily business, our cells carry out a variety of jobs, such as repairing their DNA or getting ready to divide . These jobs are carried out by distinct sets of molecular ‘machines’ that act together to do the work.
Over thousands of years of evolution, our cells appear to have developed several different sets of machinery with which to accomplish each task.
This duplication may seem wasteful, but in fact it acts as a safety net – if one pathway becomes damaged, then another can compensate. This helps to keep us healthy.
But cancer cells are a mess , genetically speaking. Some genes are faulty or missing, while others are overactive. As a result, they often have just one intact pathway for many essential functions – the others having become damaged during the cancer’s development. And this makes them vulnerable to attack.
Researchers have been trying to figure out exactly which pathways cancer cells are dependent on, as blocking them could lead to powerful treatments.
Removing the safety net
In their new paper, published in the journal Cancer Cell , Professor Ashworth and his team studied cancer cells that were lacking one of two genes - MLH1 or MSH2 – that are part of a cell’s DNA repair machinery.
Cells lacking either of these genes tend to accumulate DNA damage, which leads to further cancerous mistakes as they multiply. But the cell’s other machinery can still compensate for the lack of MLH1 or MSH2, and the cancer continues to grow and spread.
Other key components of the DNA repair machinery are proteins called DNA polymerases , which seem to be able to repair DNA in the absence of MLH1. So Professor Ashworth figured that targeting these DNA polymerases might remove this safety net, and could kill the cancer cells.
In lab experiments, the researchers took samples of human bowel cancer cells that either contained or lacked MLH1, and human womb cancer cells that contained or lacked MSH2. They then used a technique called RNA interference to ‘knock out’ the cell’s DNA polymerases.
They discovered that the cancer cells which lacked MSH2 were killed by removing a polymerase called POLB, while getting rid of another, called POLG, killed the MLH1-deficient womb cancer cells. In both cases, the researchers found that the cancer cells suffered from a toxic build-up of damaged DNA.
However, the cells that still had MSH2 and MLH1 were able to repair this damage and survive. It was only when both sets of repair genes – the DNA polymerases and either MSH2 or MLH1 – were damaged or missing, that the damage built up to lethal levels.
To draw an analogy, in each case MSH2 and MLH1 are like a belt holding up a pair of trousers, while the DNA polymerase is a pair of braces. If the belt breaks, then the trousers still stay up. But if the braces are cut as well, then disaster strikes.
Where do we go next?
This discovery is very important, as it suggests that targeting either POLB or POLG could be a useful way to treat cancers with faults in MSH2 or MLH1, respectively. And we already know this approach works – trials of PARP inhibitors, designed along the same principles, are already showing great promise in clinical trials .
At the moment, the technique the researchers used to block POLB or POLG isn’t easily transferable to the clinic. Scientists now need to find chemical compounds (i.e. drugs) that have the same effect. A few polymerase blockers have been developed so far, but they aren’t very potent so they wouldn’t be practical to use as drugs.
There is also one final interesting aspect to this research. As mentioned earlier, the scientists discovered that the combination of faulty repair genes and blocked polymerase led to a toxic build-up of a specific type of DNA damage. It’s possible to measure levels of this kind of damage, which could give a fast and accurate read-out of whether any future treatment was working. As we’ve written about before , improving how we monitor new treatments will be critical to judging their success.
Year on year, researchers like Professor Ashworth, and many of the thousands of other researchers we fund are increasing our understanding of the genetic mistakes that lie at the heart of cancer, and using this knowledge to find more effective ways to target the disease. Today’s discovery is another important step along the way.
Sarah A. Martin, Nuala McCabe, Michelle Mullarkey, Robert Cummins, Darren J. Burgess, Yusaku Nakabeppu, Sugako Oka, Elaine Kay, Christopher J. Lord, & Alan Ashworth (2010). DNA Polymerases as Potential Therapeutic Targets for Cancers Deficient in the DNA Mismatch Repair Proteins MSH2 or MLH1 Cancer Cell : 10.1016/j.ccr.2009.12.046