British researchers have found a mutation that prevents PARP inhibitors from working, it has been announced.
The mutation is found in the PARP1 protein and disrupts its ability to bind to DNA – the point at which PARP inhibitors work, according to scientists at the Institute of Cancer Research, London, UK.
The researchers say there may be more of these mutations. Several were found in animal models – but only one in humans.
They believe that the BRCA1 gene may be able to override the faulty PARP1 proteins, conducting its own DNA repair.
The findings were reported yesterday in Nature Communications.
Researcher Dr Stephen Pettitt said: “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.
“Our study has discovered one of the reasons why resistance to PARP inhibitors such as olaparib might occur. 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.”
Fellow researcher Professor Chris Lord said: “We hope our research will help doctors use the best drug right from the outset, respond quickly to early signs of resistance, and work out the best ways to combine treatments to overcome drug resistance.”
The research has been backed by Cancer Research UK and Breast Cancer Now.
Baroness Delyth Morgan, chief executive of Breast Cancer Now, said:
“Identifying specific mutations that indicate how likely breast cancer cells are to develop resistance to PARP inhibitors could help guide their use in the clinic.
“This important finding could in future allow clinicians to determine who would benefit most from these drugs, or to track when they are becoming less effective and when a change of treatment might be appropriate.”
Nature Communications 10 May 2018
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