TY - JOUR
T1 - Fatty acid synthase (FASN) signalome
T2 - A molecular guide for precision oncology
AU - Menendez, Javier A.
AU - Cuyàs, Elisabet
AU - Encinar, Jose Antonio
AU - Vander Steen, Travis
AU - Verdura, Sara
AU - Llop-Hernández, Àngela
AU - López, Júlia
AU - Serrano-Hervás, Eila
AU - Osuna, Sílvia
AU - Martin-Castillo, Begoña
AU - Lupu, Ruth
N1 - Publisher Copyright:
© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
PY - 2024/3
Y1 - 2024/3
N2 - 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.
AB - 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.
KW - cell fate
KW - ferroptosis
KW - immunotherapy
KW - metastasis
KW - mitochondrial priming
KW - molecular glues
UR - http://www.scopus.com/inward/record.url?scp=85182850426&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85182850426&partnerID=8YFLogxK
U2 - 10.1002/1878-0261.13582
DO - 10.1002/1878-0261.13582
M3 - Article
C2 - 38158755
AN - SCOPUS:85182850426
SN - 1574-7891
VL - 18
SP - 479
EP - 516
JO - Molecular Oncology
JF - Molecular Oncology
IS - 3
ER -