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Understanding why PARP inhibitors may stop working for some cancer patients

New findings could help identify patients likely to become resistant to anti-cancer drugs and aid exploring different ways to kill cancer resistant cells.

5 March 2025
Cancer cell

A new study, published in the British Journal of Cancer, by Dr Martin Higgs and team from the Department of Cancer and Genomic Sciences at the University of Birmingham, describes new understanding surrounding how cancer cells with faults in the BRCA1 gene can become resistant to poly-ADP ribose polymerase (PARP) inhibitors.

PARP inhibitors are a type of targeted cancer treatment commonly used to treat cancers caused by faults in the BRCA1 and BRCA2 genes. They work by stopping PARP from repairing damage in cancer cells, meaning the cancer cells die. BRCA1 and BRCA2 genes are tumour suppressor genes. Having a fault in these genes makes a person more susceptible to breast, ovarian and other cancers.

Whilst PARP inhibitors are usually successful for treating cancer in patients with faulty BRCA1 and BRCA2 genes initially, many patients can become resistant to these inhibitors over time. This means that the cancer cells find ways to counteract the drug, allowing them to survive even when exposed to the medication, so it is no longer effective. Therefore, research to understand the mechanisms behind this resistant is vital to ensure long term effectiveness of treatments for these cancers.

Understanding these mechanisms of resistance is crucial to improve anti-cancer therapy. If we can identify different ways that cancer cells become resistant to PARP inhibitors, then we can design tests to spot resistance before patients stop responding. By understanding the underlying basis for resistance, we can then either use existing drugs, or design new ones, to overcome the resistance and successfully treat these cancers.

Dr Martin Higgs, Department of Cancer and Genomic Sciences, University of Birmingham, lead author of the paper.

Some understanding of mechanisms that can lead to resistance already exists, including an awareness that mechanisms of resistance differ between cancers with faulty BRCA1 genes compared with faulty BRCA2 genes. This recent publication adds to the knowledge base by describing what happens when cells with mutated BRCA1 lose another DNA repair gene called SETD1A. This changes how cells express their genes, especially a gene called EME1. The researchers were able to show that this change in EME1 made cancer cells with faults in BRCA1(but not BRCA2) become resistant to PARP inhibitors. They demonstrated that this mechanism also happened in cells with faults in another DNA repair gene, ATM. This suggests that changes in EME1 may be a common resistance mechanism.

Taken together, these findings shed new light on how cancer cells become resistant to PARP inhibitors. This understanding will help identify patients who are likely to become resistant to their treatment. It will also help researchers to find new drugs to target these resistant cancer cells.

Featured staff

  • Dr Martin R. Higgs

    Associate Professor for Genomics and Rare Disease

    Staff profile for Professor Martin Higgs, Associate Professor for Genomics and Rare Disease and Deputy Director, Centre for Rare Disease Studies, Department of Cancer and Genomic Sciences, University of Birmingham

    Phone: +44 (0)121 414 8480
    Email:

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