Targeting Fatty Acid Synthase (FASN): A New Horizon in Precision Cancer Medicine

The Metabolism and Cancer Research Group at the Girona Biomedical Research Institute (IDIBGI) and the ProCURE program of the Catalan Institute of Oncology (ICO) introduces a transformative view of a cancerous protein in their recent study. Published in the journal “Molecular Oncology,” the research group highlights unexplored features of the lipogenic enzyme Fatty Acid Synthase (FASN) in cancer. The findings suggest that FASN could become a new target for precision oncology treatments.

FASN: From Metabolic Enzyme to Cancer Therapy Game Changer

FASN is an enzyme that is used by our bodies to create fat molecules from smaller building blocks. This process is normally restricted to the liver and adipose tissues, helping to convert excess carbohydrates into fat to be stored. Most cells in our body don't make their own fatty acids; they get them from the food we eat or from the fatty acids made by our liver.

“Cancer cells are hijackers of this process to fuel their growth. They can turn on FASN to make their own lipids, which helps them to resist treatments and to spread rapidly”, points out Dr. Javier Menéndez, group leader and first author of the study. This ability to make lipids on their own allows cancer cells to become more aggressive and less dependent on external nutrient sources.

“This study represents a major shift in the understanding of FASN's multifunctionality in oncology, highlighting its complex and largely unexplored role beyond lipid synthesis,” remarks Dr. Menéndez. The Girona researchers, in collaboration with the Mayo Clinic in Rochester (USA), the Institute of Research, Development, and Innovation in Biotechnology of Elche (IDiBE), and the Institut de Química Computacional i Catàlisi (IQCC) of the University of Girona, redefine the role of FASN in cancer, arguing that it should be considered a signal transducer rather than just a fat factory. FASN is like a complex switchboard that processes information within cancer cells and between these cells and their environment. This process is important from the earliest stages of cancer formation to the later spread of cancer to other parts of the body.

The “Hidden Powers” of FASN: New Possible Ways to Treat Cancer Revealed

Researchers identify four new hallmarks of FASN that contribute to cancer progression and resistance:

Unlocking cell plasticity. Cancer cells often gain the ability to change their type, which helps them grow and spread. FASN is involved in this process, not only through its well-known role in making fats but also through other functions. To stop this, scientists are looking at developing new drugs called “molecular glues” that cause the FASN protein itself to be destroyed.
Influencing cell death: Senescent “zombie” cells. Blocking FASN makes cancer cells more susceptible to a form of programmed cell death that involves the mitochondria (the powerhouses of the cell). This can be exploited by combining FASN inhibitors with other drugs called “BH3 mimetics” that stimulate mitochondrial cell death. Sometimes, cancer cells become "senescent" when they are treated with FASN inhibitors, which means that they stop growing, but don't die. These “zombie” cells are more susceptible to other treatments called “senolytics” that could be used after FASN inhibitors for a more effective therapy, creating an opportunity to design "one-two punch" sequential cancer treatments.
Evading the immune system. FASN activity helps cancer cells hide from the immune system. By inhibiting FASN, we may be able to make cancer cells more recognizable and easier to destroy by immune cells. This could increase the efficacy of immunotherapies that help the immune system target cancer cells.
Surviving under harsh conditions. FASN is critical for cancer cells to manage oxidative stress and survive, especially when they spread to areas where nutrients like fats are scarce, such as the brain. Using FASN inhibitors, we could potentially make cancer cells less able to cope with these stressful conditions and more likely to die. This is especially true when combined with certain diets or drugs that induce a type of cell death known as ferroptosis, which is iron-dependent and related to oxidative stress.

Collectively, the latest paper published by the Metabolism and Cancer group could help change our understanding of FASN's role in cancer. “Instead of seeing it simply as a component of cell metabolism that aids in cancer growth, we now recognize FASN as a multifunctional player that could be targeted in different ways to treat cancer more effectively,” exposes Dr. Menéndez. “This opens up new therapeutic avenues, including not only using classical FASN inhibitors to block fat production, but also offering new therapeutic angles to target non-traditional aspects of FASN activity to make cancer cells more vulnerable to other treatments, improve the immune system’s targeting of cancer cells, and prevent cancer cell survival during metastasis.”

This study represents a major shift in the understanding of the multifunctionality of FASN and opens the door to more precise and personalized cancer treatments for improved patient outcomes.

Reference article: Menendez, J.A., Cuyàs, E., Encinar, J.A., Vander Steen, T., Verdura, S., Llop-Hernández, À., López, J., Serrano-Hervás, E., Osuna, S., Martin-Castillo, B. and Lupu, R. (2024), Fatty acid synthase (FASN) signalome: A molecular guide for precision oncology. Mol Oncol. https://doi.org/10.1002/1878-0261.13582