A group of researchers found that loss of the neurofibromin 1 (NF1) gene reduced the response to alpelisib. The study was published in the journal Cell Reports Medicine. A research group from the Department of Biomedicine at the University of Basel has now discovered that loss of the neurofibromin 1 (NF1) gene results in a reduced response to alpelisib. The researchers also found that the dietary supplement N-acetylcysteine restores the sensitivity of cancer cells to this treatment.
Loss of genes triggers resistance
At this time, patients with advanced and metastatic breast cancer do not have effective treatment options. The PI3K signaling pathway is often overactivated in breast cancer due to mutations that promote tumor growth. The approval of the PI3K inhibitor Alpelisib was therefore eagerly anticipated.
“Unfortunately, it turns out that the drug’s success is severely limited by resistance,” says Professor Mohamed Bentyres-Alz, head of the research group. “Therefore, we urgently need to find out more about how resistance arises.”
So his team went looking for the genetic basis of resistance—in other words, trying to figure out which genes changed to make cancer cells resistant. The results: Mutations that shut down production of the NF1 protein made the tumors resistant to treatment with alpelisib. It is known that NF1 suppresses tumor growth through a variety of signaling pathways, but the gene has not yet been linked to resistance to alpelisib.
Additional experiments conducted by the researchers confirmed that loss of NF1 also causes immunity in human cancer cells and in tissues cultured from tumors. “So the absence of NF1 is the elephant in the room; it throws everything inside the cell into disarray and hinders successful treatment,” says Bentires-Alj.
A promising pairing with an expectorant
An analysis shows that the loss of NF1 affects the cells’ energy reserves: “They stop producing as much energy using the mitochondria; instead, they switch to other energy production pathways,” says Dr. Prisca auf der Maur, lead author of the study.
Given these changes, the researchers conducted experiments with the known antioxidant N-acetylcysteine, which has similar effects on energy metabolism and was therefore expected to mimic the effects of NF1 loss. This substance is a well-known dietary supplement, as well as an ingredient in many cough medicines.
Surprisingly, N-acetylcysteine had the opposite effect: it restored the effectiveness of alpelisib in resistant cancer cells. In fact, it has increased it. This occurs through further interference with another signaling pathway that also plays an important role in tumor growth, the researchers discovered through further analysis. Interestingly, loss of NF1 also plays a role in resistance to other drugs. Combination therapy with N-acetylcysteine may also be possible in these cases.
“N-acetylcysteine is a safe and widespread additive, this result is highly relevant for clinical research,” says Bentires-Alj. He believes that combining N-acetylcysteine with alpelisib may improve the treatment of advanced breast cancer. The next step is now to conduct clinical studies with breast cancer patients to confirm the positive effects observed in the laboratory.
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