Steen Travis Vander, Espinoza Ingrid, Duran Cristina, Casadevall Guillem, Serrano-Hervás Eila, Cuyàs Elisabet, Verdura Sara, Kemble George, Kaufmann Scott H, McWilliams Robert, Osuna Sílvia, Billadeau Daniel D, Menendez Javier A, Lupu Ruth
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
National Institute of Health, National Heart Lung and Blood Institute (NHLBI), Bethesda, MD 20817, USA; Lung Development and Pediatric Branch (HNH36), Bethesda, MD 20817, USA.
Neoplasia. 2025 Apr;62:101143. doi: 10.1016/j.neo.2025.101143. Epub 2025 Feb 24.
Resistance to mitochondrial apoptosis is a major driver of chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, pharmacological manipulation of the mitochondrial apoptosis threshold in PDAC cells remains an unmet therapeutic goal. We hypothesized that fatty acid synthase inhibitors (FASNis), a family of targeted metabolic therapeutics recently entering the clinic, could lower the apoptotic threshold in chemoresistant PDAC cells and be synergistic with BH3 mimetics that neutralize anti-apoptotic proteins. Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain. The extent of NADPH accumulation, a consequence of FASN inhibition, paralleled the sensitivity of PDAC cells to the apoptotic effects of TVB FASNis in conventional PDAC cell lines that naturally express varying levels of FASN. FASN inhibition dramatically increased the sensitivity of "FASN-high" expressing PDAC cells to the BCL2/BCL-X/BCL-W inhibitor ABT-263/navitoclax and the BCL2-selective inhibitor ABT-199/venetoclax, both in vitro and in in vivo xenografted tumors. The ability of TVB FASNis to shift the balance of pro- and anti-apoptotic proteins and thereby push PDAC cells closer to the apoptotic threshold was also observed in cell lines developed from patient-derived xenografts (PDXs) representative of the classical (pancreatic) transcriptomic subtype of PDAC. Experiments in PDAC PDXs in vivo confirmed the synergistic antitumor activity of TVB-3664 with navitoclax and venetoclax, independent of the nature of the replication stress signature of patient-derived PDAC cells. The discovery that targeted inhibition of FASN is a metabolic perturbation that sensitizes PDAC cells to BH3 mimetics warrants further investigation to overcome resistance to mitochondrial apoptosis in PDAC patients.
对线粒体凋亡的抗性是胰腺导管腺癌（PDAC）化疗耐药的主要驱动因素。然而，对PDAC细胞中线粒体凋亡阈值进行药理学调控仍是一个尚未实现的治疗目标。我们推测，脂肪酸合酶抑制剂（FASNis）是一类最近进入临床的靶向代谢疗法，它可以降低化疗耐药的PDAC细胞的凋亡阈值，并与中和抗凋亡蛋白的BH3模拟物产生协同作用。对临床级FASNi TVB-2640（地尼伐他汀）的两种类似物TVB-3166和TVB-3664进行的计算研究证实，它们与FASN酮酰还原酶结构域结合时对NADPH具有非竞争性作用。FASN抑制导致的NADPH积累程度与传统PDAC细胞系中PDAC细胞对TVB FASNis凋亡效应的敏感性平行，这些细胞系自然表达不同水平的FASN。FASN抑制显著提高了“FASN高表达”的PDAC细胞对BCL2/BCL-X/BCL-W抑制剂ABT-263/维奈托克和BCL2选择性抑制剂ABT-199/ Venetoclax的敏感性，无论是在体外还是在体内异种移植肿瘤中。在源自代表PDAC经典（胰腺）转录组亚型的患者来源异种移植（PDX）的细胞系中，也观察到TVB FASNis能够改变促凋亡蛋白和抗凋亡蛋白的平衡，从而使PDAC细胞更接近凋亡阈值。在体内PDAC PDX实验中证实了TVB-3664与维奈托克和venetoclax的协同抗肿瘤活性，这与患者来源的PDAC细胞的复制应激特征性质无关。靶向抑制FASN是一种使PDAC细胞对BH3模拟物敏感的代谢扰动，这一发现值得进一步研究，以克服PDAC患者对线粒体凋亡的抗性。
