Researchers at The Institute of Cancer Research, London, have increased our understanding of how cancer drugs called PARP inhibitors stop working in people with secondary breast cancer. This research could ultimately help predict who’s more likely to respond to these drugs, and could lead to better ways to treat the disease.
PARP inhibitors and drug resistance
PARP inhibitors are a type of targeted therapy that is used to treat breast cancers with an altered BRCA1 or BRCA2 gene.
Cancer cells with changes in the BRCA1/2 genes can’t fix damaged DNA through a process known as homologous recombination (HR). PARP inhibitors cause a type of DNA damage that only cells with normal forms of BRCA1 and BRCA2 can repair.
This means that PARP inhibitors kill cancer cells with changes in the BRCA1/2 genes , but leave normal cells relatively unharmed.
Unfortunately, breast cancer cells can sometimes become resistant to PARP inhibitors. Researchers have previously found multiple ways cancer cells can evade the effects of PARP inhibitors in lab experiments. But, until now, it was unclear how PARP inhibitor resistance happens in people with secondary breast cancer.
Analysing cancer DNA
Professors Andrew Tutt and Chris Lord, from the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research (ICR) and the Research Unit at King’s College London, analysed tumour DNA of 47 people with secondary breast cancer that was, or became resistant to, PARP inhibitors.
Using an advanced technique called ‘ctDNA profiling’, the researchers looked at short pieces of DNA produced by cancer cells that have found their way into the bloodstream.
The team found that in 60% of people with PARP inhibitor resistance, the altered BRCA gene had changed so that the gene could work again. These new ‘reversion’ mutations meant that the cancer cells could survive the effects of PARP inhibitors.
The researchers also found that some people with PARP inhibitor resistance had changes to other genes known to stop PARP inhibitors from working, such as changes in a gene called TP53BP1. These changes and the BRCA gene ‘reversions’ could happen in the same person.
Looking ahead
The team noticed that the disease progressed much quicker in people whose cancer showed signs of BRCA1/2 gene reversions before starting treatment. In the future, this information could potentially help inform which people gain the most or the least from these drugs.
Andrew and Chris hope that by understanding what causes PARP inhibitor resistance, they could eventually identify better ways of treating breast cancer. And this work has already started in their lab.
Professor Andrew Tutt, Professor of Breast Oncology and Director of the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, London, and our Research Unit at Kings College London, said:
The discovery that PARP inhibitors could have benefit for BRCA-mutated cancers – which was made here at the ICR – has had a monumental impact on patients’ lives. However, we know there’s more work to be done as some people develop resistance to the drugs and sadly see their cancer progress. Our research has uncovered clues as to why that may be, and we hope to use this knowledge to develop tests that can detect who is at greatest risk of becoming resistant to PARP inhibitor treatment, develop new treatments to tackle resistance, and take action before their breast cancer progresses.
Professor Andrew Tutt
This research was published in Annals of Oncology and funded by Breast Cancer Now, Cancer Research UK, the Breast Cancer Research Foundation and a Marie Slkodowska-Curie Fellowship.