N-acetylcysteine To Combat Resistance in Breast Cancer

Numerous cancer treatments fall short of expectations. The development of drug resistance in malignancies is a frequent cause of this. This is the case, for instance, with the medicine alpelisib, which has just received approval in Switzerland for use as a treatment for advanced breast cancer.
The deletion of the neurofibromin 1 (NF1) gene decreases the response to alpelisib, according to new research from the University of Basel’s Department of Biomedicine. The dietary supplement N-acetylcysteine, according to the study’s findings, helps cancer cells regain their sensitivity to this therapy. On April 11, the findings were released in the journal Cell Reports Medicine.

There are currently few viable therapeutic options available for patients with advanced and metastatic breast cancer. Breast cancer frequently has an overactive PI3K signaling system because of mutations that encourage tumor growth. Therefore, the approval of the PI3K inhibitor Alpelisib was eagerly awaited.

“Unfortunately, it turned out that the success of the medication is severely limited by resistance,” says Professor Mohamed Bentires-Alj, head of the research group. “Hence, we urgently need to find out more about how resistance arises.”

His team next set out to identify the genetic basis for the resistance or the genes that had altered to make cancer cells resistant. They discovered that the tumors were resistant to therapy with alpelisib due to mutations that turned off the NF1 protein’s production. Although NF1 is known to inhibit the growth of malignancies via a number of signaling pathways, alpelisib resistance had not yet been connected to the gene.

The lack of NF1 also results in resistance in human cancer cells and tissue generated from tumors, further study by the team has shown. “So the absence of NF1 is the elephant in the room; it throws everything into disarray within the cell and hinders successful treatment,” says Bentires-Alj.

An analysis shows that the loss of NF1 affects the cell’s energy reserves: “They stop producing as much energy using mitochondria; instead, they switch to other energy production pathways,” says the lead author of the study, Dr. Priska Auf der Maur.

Given these modifications, the researchers tested the impacts of NF1 depletion using the well-known antioxidant N-acetylcysteine, which has a comparable impact on energy metabolism. This chemical is a popular nutritional supplement and a common component in cough syrups.

Contrary to expectations, N-acetylcysteine restored the efficacy of alpelisib in cancer cells that were resistant to the drug. In fact, it made it worse. The researchers found that this occurs via an extra intervention in a signaling pathway that likewise has a significant impact on tumor growth. It’s interesting to note that drug resistance is also influenced by the depletion of NF1. In these circumstances, combination therapy with N-acetylcysteine may potentially be an option.

“As N-acetylcysteine is a safe and widespread additive, this result is highly relevant for clinical research,” says Bentires-Alj. He thinks that a combination of N-acetylcysteine with alpelisib could improve the treatment of advanced breast cancer. The next step would now be to run clinical studies with breast cancer patients to confirm the positive effects observed in the lab.

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