Weill Cornell Medical College, New York, NY, USA.
University of Campinas, Piracicaba, Brazil.
Sci Signal. 2024 Apr 9;17(831):eadh1922. doi: 10.1126/scisignal.adh1922.
Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer; however, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by increased de novo synthesis of fatty acids due to overexpression of fatty acid synthase (FASN), making this enzyme a therapeutic target for prostate cancer. Inhibition of FASN results in increased intracellular amounts of ceramides and sphingomyelin, leading to DNA damage through the formation of DNA double-strand breaks and cell death. We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.
雄激素剥夺疗法（ADT）是前列腺癌的主要治疗方法；然而，ADT 的耐药性不可避免地会发展，导致去势抵抗性前列腺癌（CRPC）。由于脂肪酸合酶（FASN）的过度表达，前列腺癌的进展标志着新合成脂肪酸的增加，使这种酶成为前列腺癌的治疗靶点。FASN 的抑制导致细胞内神经酰胺和鞘磷脂含量增加，通过形成 DNA 双链断裂和细胞死亡导致 DNA 损伤。我们发现，将 FASN 抑制剂与聚 ADP 核糖聚合酶（PARP）抑制剂奥拉帕利联合使用，通过阻断 DNA 损伤修复诱导细胞死亡，比单独使用任何一种药物都能更显著地降低细胞生长。用 PARP 和 FASN 联合治疗的人 CRPC 类器官体积更小，细胞增殖减少，凋亡和坏死增加。总之，这些数据表明，通过损害 DNA 损伤修复，靶向 FASN 增加了 PARP 抑制剂的治疗效果，表明应该探索针对 CRPC 的联合治疗方法。
