Metastatic pancreatic neuroendocrine tumors (PNET) remain an unmet clinical problem. Chronologic treatment in PNETs includes observation (watchful protocol), surgery, targeted therapy, and chemotherapy. However, increasing evidence illustrates that the outcomes of targeted therapeutic options for the treatment of advanced PNETs show minimal response. The FDA-approved mTOR inhibitor everolimus does not shrink these tumors. It only delays disease progression in a subset of patients, while a significant fraction acquires resistance and shows disease progression. Thus, there is a need for more effective targeted approaches to sensitize PNETs to everolimus for better treatment outcomes. Previously, we showed that mTOR regulator p21 activated kinase 4 (PAK4) and nicotinamide adenine dinucleotide biosynthesis enzyme nicotinamide phosphoribosyl transferase (NAMPT) were aberrantly expressed in PNET tissue and promoted everolimus resistance. In this report, we demonstrate that PAK4-NAMPT dual inhibitor KPT-9274 can synergize with everolimus (growth inhibition, colony suppression, and glucose uptake assays). KPT-9274-everolimus disrupted spheroid formation in multiple PNET models. Molecular analysis showed alteration of mTORC2 through downregulation of RICTOR as a mechanism supporting synergy with everolimus in vitro . KPT-9274 suppressed β-catenin activity via inhibition of PAK4, highlighting the cross-talk between Rho GTPases and Wnt signaling in PNETs. KPT-9274, given at 150 mg/kg in combination with sub-MTD everolimus (2.5 mg/kg), significantly suppressed two PNET-derived xenografts. These studies bring forward a well-grounded strategy for advanced PNETs that fail to respond to single-agent everolimus.

中文翻译：

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PAK4-NAMPT 双重抑制使胰腺神经内分泌肿瘤对依维莫司敏感

转移性胰腺神经内分泌肿瘤 (PNET) 仍然是一个未解决的临床问题。PNET 的时间治疗包括观察（观察方案）、手术、靶向治疗和化疗。然而，越来越多的证据表明，用于治疗晚期 PNET 的靶向治疗方案的结果显示出最小的反应。FDA 批准的 mTOR 抑制剂依维莫司不会缩小这些肿瘤。它只会延迟一部分患者的疾病进展，而相当一部分患者会获得抗药性并显示出疾病进展。因此，需要更有效的靶向方法来使 PNET 对依维莫司敏感，以获得更好的治疗结果。之前，我们发现 mTOR 调节因子 p21 活化激酶 4 (PAK4) 和烟酰胺腺嘌呤二核苷酸生物合成酶烟酰胺磷酸核糖基转移酶 (NAMPT) 在 PNET 组织中异常表达并促进依维莫司耐药。在本报告中，我们证明 PAK4-NAMPT 双重抑制剂 KPT-9274 可以与依维莫司协同作用（生长抑制、菌落抑制和葡萄糖摄取测定）。KPT-9274-依维莫司破坏了多个 PNET 模型中的球体形成。分子分析显示通过下调 RICTOR 改变 mTORC2 作为体外支持与依维莫司协同作用的机制。KPT-9274 通过抑制 PAK4 抑制 β-连环蛋白活性，突出了 PNET 中 Rho GTPase 和 Wnt 信号传导之间的串扰。KPT-9274，以 150 mg/kg 与亚 MTD 依维莫司 (2.5 mg/kg) 联合给药，显着抑制了两个 PNET 衍生的异种移植物。这些研究为无法对单剂依维莫司做出反应的高级 PNET 提出了一个有充分根据的策略。