Combating Chemoresistance by Targeting DNA Repair

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In 2012, the most recent year for which the information is available, there were 8.2 million cancer-related deaths worldwide. Chemotherapy is a common treatment resort, but it’s by no means a magic bullet, and this is often due to chemoresistance. This latest Chemunicate graphic, made on behalf of Thomas Fleming at the University of Oxford, looks at how understanding this process can help chemists develop new drugs to tackle the problem. 

To understand what chemoresistance is, we first need to understand what a cancer cell is. The cells in your body are continually dividing, and every time they do so their DNA must be unzipped and copied. This copying process isn’t perfect; just as if you had to copy out the entirety of War and Peace word for word you’d probably make the odd mistake, your body’s DNA copying machinery has the occasional mishap. Luckily, your cells have tools and processes at their disposal which, like cellular proofreaders, can spot these mistakes and correct them.

Still, even these repair processes can miss errors, and over time they can accumulate. They’re largely benign, but in a cancerous cell these changes have broken the control over cell division. This means that they can then divide constantly and uncontrollably, eventually forming large abnormal growths of cells called tumours. These tumours can cause a number of problems in the body.

To try and wrest back control over the cell division of cancer cells different treatments can be used. Radiotherapy uses beams of high energy to target cancer cell DNA, whereas chemotherapy involves the administering of anti-cancer drugs. One of the most commonly known anticancer drugs is called cisplatin, which works by forming a bridge between DNA strands in cancer cells, preventing them from unzipping and replicating. This renders the cancer cell incapable of making copies of itself, slowing or even stopping the growth of the tumour.

However, there’s a problem. The DNA repair processes, the cellular proofreaders that can correct errors after DNA copying, can also remove the blocks created by chemotherapy. Thus the cancer cells turn the body’s own DNA repair mechanisms against it, using them to cast off the sections of DNA that chemotherapy drugs have acted on and restoring their own ability to replicate. The consequence of this is that increasingly high doses of the chemotherapy drugs are needed to destroy the cancer – and sometimes even this is not enough.

Luckily, cancer cell reliance on DNA repair mechanisms to resist the effects of chemotherapy can also be used against them. Because they can become dependent on a particular repair mechanism to remove replication blocks formed by chemotherapy drugs, scientists are trying to develop ways of blocking these particular mechanisms in cancerous cells, preventing the repair from taking place.

One such drug is olaparib, which inhibits a DNA repair protein called PARP. Olaparib works by trapping PARP onto DNA and preventing it from completing its repair process. This means there is a better chance that the replication blocks introduced by chemotherapy drugs remain in place. Scientists are now working on new drugs which can block more DNA repair processes in the hope that these could be used to treat chemoresistance in a wider range of cancers, increasing the chances of patient survival.

This is a commissioned Chemunicate graphic produced for Thomas Fleming of the University of Oxford. Chemunicate creates commissioned graphics for chemistry researchers and institutions. If you’re interested in having a graphic made based on your research or some other topic, find out more here.

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