CRISPR study finds resistance mutations to key cancer drugs

DNA mutations that give tumours resistance to a new class of breast and ovarian cancer drugs have been discovered. 

An international team of scientists used the CRISPR/Cas9 genome editing system to create mutations in a gene called PARP1. This gene plays an important in the repair of DNA, a key function of any living cell.

Certain cancer drugs, known as PARP inhibitors, target this repair pathway in cancerous cells, in order to slow or prevent a tumour's growth. Some of these inhibitors – such as olaparib, a drug to treat ovarian cancer – are available on the NHS for patients with the inherited BRCA mutations. PARP inhibitors have been found to be especially promising when patients' tumours have mutations in other DNA repair genes. 

However, mutations in the PARP1 gene in cancerous cells can make them become resistant to the inhibitors. In this study, published in Nature Communications, the researchers were able to observe the effects of the PARP1 mutations on the sensitivity of cancer cells to PARP inhibitors.  

'PARP inhibitors are hugely exciting new drugs which are especially effective in women with BRCA mutations – but unfortunately as with many other treatments it is common for cancer cells to eventually develop resistance,' said Dr Stephen Pettitt at the Institute of Cancer Research in London, and a study author. 'Our study has discovered one of the reasons why resistance to PARP inhibitors such as olaparib might occur.'

The mutations in PARP1 were created artificially using genome editing and studied in the laboratory. Further investigations in real patients' samples is necessary to see whether the results hold out in a clinical context. However, the team hopes that understanding the molecular mechanism of resistance in a patient's tumour could help to inform their doctors' course of action for treating it. 

'Testing for the mutations we have identified could offer even more personalised treatment for women with breast and ovarian cancer, by allowing doctors to judge whether and for how long olaparib should be used,' said Dr Pettitt. 

Baroness Delyth Morgan, chief executive of Breast Cancer Now, a funder of the study, added: 'Resistance to breast cancer drugs is a major hurdle that we must overcome if we are to stop women dying from this devastating disease. It is vital that we understand exactly how and when cancer cells begin to adapt to and resist treatment, so that we can remain one step ahead of often elusive cancer cells.'