A team from Gustave Roussy and Paris-Saclay University has just highlighted a new therapeutic target for breast and ovary cancers linked to BRCA1/2 changes. Their discovery, published in Nature Communicationsopens the way to innovative treatments for patients resistant to current therapies.
BRCA1/BRCA2 cancers: the problem of resistance to treatments
Mutations of the BRCA1 and BRCA2 genes affect several thousand people each year. They strongly increase the risk of developing breast or ovary cancer, sometimes from a young age. For these patients and their families, the disease often arrives as an unexpected cleaver.
Today, parp inhibitors are the reference targeted therapy. They exploit the weakness created by the BRCA mutation to cause the death of the tumor cells. In detail, these drugs block the action of enzymes called Poly (ADP-Ribose) Polymerases (the Parp) human, which contribute to repair damaged DNA in cells (both normal and cancerous cells) during cell division. Thanks to the blocking of PARP proteins, damaged DNA in cancer cells cannot be repaired, which results in the death of cancer cells.
But this strategy knows its limits: over time, some tumors manage to get around the treatment. Resistance then appears as a therapeutic dead end, leaving many patients without an effective option.
A French team identifies a new target
It is in this context that the work of the laboratory of Dr Sophie Postel-Vinay in Gustave Roussy is taking place. The researchers identified a key enzyme, ADAR1, which could be exploited as therapeutic target in the mutated cancers BRCA1/2. They have shown that when this enzyme is inhibited, the tumor cells deficient in BRCA1/2 accumulate damage in their DNA. This instability then triggers an internal autoimmune reaction, toxic to cancer cells, and leads to their destruction.
This approach is based on the principle of synthetic lethality. Concretely, it is a question of combining two distinct weaknesses: the mutation of the BRCA1/2 genes and the inhibition of the ADAR1 enzyme. Taken separately, none of these faults is enough to kill tumor cells. But when they are gathered, they specifically lead to the death of cancer cells with mutation, while preserving healthy cells. Researchers from the Dr Sophie Postel-Vinay laboratory have already been able to confirm this approach in several experimental models.
Hope is nevertheless very real. As Roman Chabanon, first author of the “Study:” underlines: “The discovery of this new approach to synthetic lethality opens up prospects for the treatment of aggressive cancers, such as triple-negative breast cancer which often affects young women, and for which there is no therapeutic alternative today when the tumor resists targeted therapies“.
Towards new therapies for dead end patients
These results are a decisive first step, but the path is still long before seeing the treatment available in clinic. Additional work will be necessary to transform this discovery into a drug administered to patients, as confirmed by Roman Chabanon: “We hope that ADAR1 inhibitors will soon be able to be developed and evaluated in the context of clinical trials in patients with mutated cancers BRCA1/2 which do not respond to conventional treatments “.
For patients and their loved ones, each advance of this type is a tangible sign that research continues to progress, and that a more favorable future is possible even in situations where the therapeutic arsenal seems exhausted.