A team of researchers from the ProCURE program at the Catalan Institute of Oncology (ICO) Girona-Institute of Biomedical Research of Girona (IDIBGI), in collaboration with the Mayo Clinic in the United States, has identified a new therapeutic approach to treat pancreatic cancer, one of the deadliest diseases and most resistant to current treatments. The results, published in the journal Neoplasia, show that combining inhibitors of the FASN enzyme with BH3 mimetic drugs could overcome this tumor’s resistance to apoptosis, a process also known as “cellular suicide,” which is key to eliminating damaged or diseased cells.
The key finding of the research is that inhibiting fatty acid synthase (FASN), essential for fat production in tumor cells, weakens their survival capacity in hostile environments. “By blocking FASN, we push cancer cells to the brink of death, making them extremely vulnerable to BH3 mimetics, a type of drug designed to activate apoptosis,” explains Javier A. Menéndez, co-director of the study at ICO-Girona and leader of the Metabolism and Cancer research group at IDIBGI. “This combination therapy can overcome the resistance barrier that has so far limited the effectiveness of many treatments for pancreatic cancer,” adds Ruth Lupu, co-director of the study from Mayo Clinic in Rochester (USA).
A metabolic approach to defeating pancreatic cancer
Pancreatic cancer cells activate FASN as a survival mechanism in a low-oxygen and nutrient-poor environment, typical of this tumor, which is surrounded by a massive and compact stromal tissue. Although clinical FASN inhibitors such as denifanstat (TVB-2640) exist, their efficacy in clinical trials has been limited when used alone. However, this study demonstrates that combining FASN inhibition with BH3 mimetics triggers a “domino effect” that shifts the balance toward cell death.
“The key lies in the balance between pro-death and anti-death proteins,” explain IDIBGI researchers Elisabet Cuyàs and Sara Verdura. “Cancer cells produce large amounts of anti-death proteins to resist treatments, but with this strategy, we force them into a critical point with an overwhelming amount of pro-death proteins where BH3 mimetics can act with maximum effectiveness.”
Computational science and experimental validation
The study also employed advanced computational tools to analyze the interaction of FASN inhibitors with their therapeutic target. Using structural models generated by AlphaFold2 and molecular docking simulations, researchers led by Sílvia Osuna from the Institute of Computational Chemistry and Catalysis (IQCC) at the University of Girona predicted that blocking FASN could induce an accumulation of NADPH. The researchers confirmed that this accumulation is the metabolic stress signal that makes tumor cells more susceptible to BH3 mimetics.
In vitro assays on tumor cells and in vivo experiments with animal models confirmed that inhibiting fatty acid synthesis alters the balance between pro-apoptotic and anti-apoptotic proteins. As a result, an increased sensitivity of cancer cells to drugs such as navitoclax (ABT-263) and venetoclax (ABT-199) was observed. These drugs are approved for certain blood cancers and are currently under development for use in solid tumors.
Towards new clinical trials
The research team also tested this combination in preclinical trials using patient-derived animal models representative of different molecular subtypes of pancreatic cancer, observing a significant reduction in tumor growth. “This breakthrough paves the way for future clinical trials evaluating the impact of this new combination therapy in the treatment of patients with this devastating disease,” conclude the study authors.
Reference article: Steen TV, Espinoza I, Duran C, Casadevall G, Serrano-Hervás E, Cuyàs E, Verdura S, Kemble G, Kaufmann SH, McWilliams R, Osuna S, Billadeau DD, Menendez JA, Lupu R. Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer. Neoplasia. 2025 Feb 24;62:101143. doi: 10.1016/j.neo.2025.101143. Epub ahead of print. PMID: 39999714.
