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Fatty acid synthase (FASN) signalome: A molecular guide for precision oncology
Javier A Menendez1,2, Elisabet Cuyàs1,2, Jose Antonio Encinar3
1Metabolism & Cancer Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Girona, Spain.
Abstract:
The initial excitement generated more than two decades ago by the discovery of drugs targeting fatty acid synthase (FASN)-catalyzed de novo lipogenesis for cancer therapy was short-lived. However, the advent of the first clinical-grade FASN inhibitor (TVB-2640; denifanstat), which is currently being studied in various phase II trials, and the exciting advances in understanding the FASN signalome are fueling a renewed interest in FASN-targeted strategies for the treatment and prevention of cancer. Here, we provide a detailed overview of how FASN can drive phenotypic plasticity and cell fate decisions, mitochondrial regulation of cell death, immune escape and organ-specific metastatic potential. We then present a variety of FASN-targeted therapeutic approaches that address the major challenges facing FASN therapy. These include limitations of current FASN inhibitors and the lack of precision tools to maximize the therapeutic potential of FASN inhibitors in the clinic. Rethinking the role of FASN as a signal transducer in cancer pathogenesis may provide molecularly driven strategies to optimize FASN as a long-awaited target for cancer therapeutics.
Insights
Fatty acid synthase (FASN) inhibitors show renewed promise for cancer treatment. Understanding FASN
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Fatty acid synthase (FASN) is a key enzyme in de novo lipogenesis.
- Early FASN-targeted cancer therapies faced limitations, dampening initial excitement.
- Recent advances in FASN inhibitors and signalome understanding are revitalizing interest.
Purpose of the Study:
- To provide a comprehensive overview of FASN's role in cancer.
- To explore FASN-targeted therapeutic strategies and challenges.
- To re-evaluate FASN as a signaling transducer for optimized cancer therapy.
Main Methods:
- Review of current literature on FASN biology and therapeutics.
- Analysis of FASN's role in phenotypic plasticity, cell fate, and mitochondrial regulation.
- Discussion of therapeutic approaches and limitations of FASN inhibitors.
Main Results:
- FASN influences phenotypic plasticity, cell fate, and mitochondrial regulation of cell death.
- FASN contributes to immune escape and organ-specific metastasis.
- Current FASN inhibitors have limitations, and precision tools are lacking.
Conclusions:
- Rethinking FASN's role as a signal transducer is crucial.
- Optimizing FASN-targeted strategies requires addressing current therapeutic challenges.
- FASN holds potential as a long-awaited cancer therapeutic target.
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