Basel – In the case of advanced breast cancer, treatment often fails because the cancer cells become resistant to the therapy. Basel researchers have now uncovered a mechanism behind it and found a possible solution to the problem: a therapy in combination with a known antioxidant that is often used as an expectorant.
Many cancer therapies do not bring the hoped-for results – the reason for this is often that the tumors develop resistance to the drug. For example, with alpelisib, an active substance that has been approved in Switzerland for the treatment of advanced breast cancer for a few years. A research group at the University of Basel’s Department of Biomedicine has now discovered that the loss of the gene neurofibromin 1 (NF1) leads to a reduced response to the drug alpelisib. The researchers also discovered that the dietary supplement N-acetylcysteine made the cancer cells receptive to this therapy. The results were recently published in the journal Cell Reports Medicine.
Loss of gene triggers resistance
Alpelisib has an inhibitory effect on the so-called PI3K signaling pathway, which is often overactivated by mutations in breast cancer and thus promotes the formation of tumors. There are still no effective treatment methods for patients with these mutations, especially if the breast cancer is advanced and metastases are forming. The approval of alpelisib was therefore associated with great expectations.
“Unfortunately, however, it turned out that the success of the drug is severely limited by resistance,” says Prof. Dr. Mohamed Bentires-Alj, head of the research group. “Therefore, there is an urgent need to find out more about the emergence of resistance.”
His team therefore looked for the genetic basis of resistance, i.e. for those genes whose modification makes cancer cells resistant. The result: mutations that switched off the protein NF1 made the tumors resistant to treatment with alpelisib. NF1 is known to suppress tumor growth through various signaling pathways, but the gene has not yet been linked to resistance to alpelisib.
Further experiments by the researchers confirmed that the loss of NF1 also leads to resistance in human cancer cells and tissue grown from tumors. “So the lack of NF1 is the elephant in the room that messes everything up in the cell and prevents the success of the therapy,” says Bentires-Alj.
Promising combination with cough suppressant
An analysis showed that the loss of NF1 has an impact on the energy balance of the cell: “You no longer produce as much energy with the help of mitochondria, but switch to other ways of energy production,” says the first author of the study, Dr. Priska on the Maur.
Because of these changes, the researchers conducted experiments with the well-known antioxidant N-acetylcysteine, which has a similar effect on energy metabolism and was therefore intended to mimic the effects of NF1 loss. The substance is a well-known dietary supplement and often a component of expectorant medication.
Surprisingly, N-acetylcysteine had the opposite effect: it restored and even potentiated the effects of alpelisib in resistant cancer cells. This is done through an additional intervention in another signaling pathway, which also plays an important role in tumor growth, as the researchers found out through further analysis. Interestingly, the loss of NF1 also plays a role in resistance to other drugs. These resistances could possibly also be combated by combination treatment with N-acetylcysteine.
“Since N-acetylcysteine is a safe and widely used additive, this result is very relevant for clinical research,” says Bentires-Alj. He thinks that combining N-acetylcysteine with alpelisib could improve the treatment of advanced breast cancer. The next step would now be to confirm the positive effects observed in the laboratory in clinical studies with breast cancer patients. (University of Basel/mc/ps)
Originalpublikation
Priska Auf der Maur et al.
N-acetylcysteine overcomes NF1-loss-driven resistance to PI3K alpha inhibition in breast cancer.
Cell Reports Medicine (2023), doi: 10.1016/j.xcrm.2023.101002
Research group Prof. Dr. Mohamed Bentires-Alj
University of Basel