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.

中文翻译：

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脂肪酸合酶 (FASN) 信号组：精准肿瘤学的分子指南

二十多年前，人们因发现针对脂肪酸合酶 (FASN) 催化的从头脂肪生成用于癌症治疗的药物而产生的最初兴奋是短暂的。然而，第一个临床级 FASN 抑制剂（TVB-2640；denifanstat）的出现，目前正在各种 II 期试验中进行研究，以及在理解 FASN 信号组方面取得的令人兴奋的进展，正在激发人们对 FASN 靶向策略的新兴趣用于治疗和预防癌症。在这里，我们详细概述了 FASN 如何驱动表型可塑性和细胞命运决定、细胞死亡的线粒体调节、免疫逃逸和器官特异性转移潜力。然后，我们提出了多种针对 FASN 的治疗方法，以解决 FASN 治疗面临的主要挑战。其中包括当前 FASN 抑制剂的局限性以及缺乏精密工具来最大限度地发挥 FASN 抑制剂在临床中的治疗潜力。重新思考 FASN 作为癌症发病机制中信号转导器的作用可能会提供分子驱动策略，以优化 FASN 作为癌症治疗期待已久的靶点。