Breast cancer is the most common cancer in the UK, with up to 10% of hereditary cases due to inheriting a faulty cancer-causing gene, for example, mutations in the BRCA1 gene. Individuals with BRCA1 mutations are at high risk of developing breast cancer, and often opt for prophylactic breast removal, as was reported for Hollywood actress Angelina Jolie. Previous research in Professor Steve Jackson’s Group at the Gurdon Institute led to the development of PARP inhibitors, a new class of cancer therapy which is highly effective in treating cancers with these mutations. Unfortunately, drug resistance is a common response, and so his group set out to establish how this resistance might develop.
Using state-of-the-art CRISPR gene editing technology, the researchers scanned the human genome for factors which, when mutated, could cause drug resistance in cells that lacked BRCA1. One of these factors was the previously uncharacterised Shieldin complex.
BRCA1 is critical for performing the accurate type of DNA repair known as homologous recombination (HR). This is counterbalanced by an opposing ‘error-prone’ repair pathway known as non-homologous end-joining (NHEJ). The researchers identified Shieldin as a new component of the NHEJ pathway. BRCA1-negative cells rely on this error-prone DNA repair pathway, which makes them susceptible to PARP inhibitors. If Shieldin is removed from these cells, the imbalance between the repair pathways is reversed, restoring the ability of the cell to perform DNA repair by HR, overcoming the toxicity of PARP inhibitors and therefore leading to drug resistance. The study went on to show that resistance to PARP inhibitors can lead the same cancer cells to develop vulnerabilities to alternative cancer treatments, such as radiotherapy or platinum-based chemotherapy.
