Carriers of a hereditary mutation in the BRCA1 gene have a highly increased risk of developing breast and ovarian cancer. This is because BRCA1 does not function in this population, which means that DNA breaks are not repaired properly. This leads to various errors in the DNA that can cause tumor growth. A new study, led by Oncode Investigator Sylvie Noordermeer in collaboration with Haico van Attikum (both LUMC) and others, and published today in Molecular Cell - identifies a new starting point to treat tumors with a BRCA1 mutation.
What the researchers discovered is that loss of the protein EXO1 leads to the death of BRCA1-mutated tumor cells, but not healthy cells. It turns out that this specific cell death occurs because the loss of EXO1 disables an alternative mechanism for repairing DNA breaks. As a result, DNA breaks remain unrepaired and the amount of DNA damage becomes so high that the cells die.
'Through this research, we now better understand how DNA-double strand breaks are repaired, which has important implications for the fundamental understanding of DNA repair but moreover holds great promise for better therapies for patients with certain forms of hereditary breast of ovarian cancer' says Noordermeer.
Oncode Institute has provided the initial funding of this project, which resulted in important preliminary data that was essential to further obtain KWF-funding. The project and its future directions benefited from collaborations within Oncode, with Oncode Investigator Jos Jonkers (NKI) and Edwin Cuppen (who was an Oncode Investigator until 2022).
Further research will focus on finding chemicals that inactivate EXO1 and could perhaps be used as a new drug to treat this large group of patients. Oncode Institute is currently actively involved in translating these fundamental findings into direct clinical application.
Read the full publication in Molecular Cell.