Credits: https://pubmed.ncbi.nlm.nih.gov/37044095/

Cancer therapies often fail to produce desired results due to tumors developing resistance to medication. Alpelisib, a drug approved for advanced breast cancer treatment in Switzerland, is no exception. Researchers from the University of Basel’s Department of Biomedicine have discovered that the loss of the neurofibromin 1 (NF1) gene is linked to reduced response to alpelisib. The study, published in Cell Reports Medicine, also shows that the dietary supplement N-acetylcysteine can restore cancer cells’ sensitivity to this treatment.

Effective treatments for patients with advanced and metastatic breast cancer are limited. Mutations promoting tumor development often cause the PI3K signaling pathway to be overactive in breast cancer. Alpelisib, a PI3K inhibitor, was highly anticipated as a possible solution. However, Professor Mohamed Bentires-Alj’s team sought the genetic basis of resistance, trying to identify which genes turned cancer cells resistant. They discovered that mutations that stop production of the NF1 protein made tumors resistant to alpelisib. While NF1 suppresses tumor growth through various signaling pathways, it had not previously been linked to alpelisib resistance.

The researchers’ additional experiments confirmed that loss of NF1 causes resistance in human cancer cells and tissue cultured from tumors. An analysis revealed that NF1 loss impacts the cell’s energy reserves. Consequently, the researchers tested N-acetylcysteine, a known antioxidant that has similar effects on energy metabolism to NF1 loss. Unexpectedly, it restored the effectiveness of alpelisib in resistant cancer cells and increased it. This occurs through intervention in another signaling pathway that also contributes to tumor growth, as further analysis shows. It is interesting to note that loss of NF1 also affects resistance to other medications, raising the possibility of combination therapy with N-acetylcysteine.

As N-acetylcysteine is safe and widely used, this result is highly relevant to clinical research. Combining N-acetylcysteine with alpelisib could improve advanced breast cancer treatment. Clinical studies with breast cancer patients would be the next step to confirm the positive effects observed in the lab.