Azar Ibrahim, Khan Husain Yar, Bannoura Sahar F, Gandhi Nishant, Uddin Md Hafiz, Nagasaka Misako, Gong Jun, Nazha Bassel, Choucair Khalil, Vojjala Nikhil, Khushman Moh'd M, Soares Heloisa P, El-Deiry Wafik S, Philip Philip Agop, El-Rayes Bassel, Chen Herbert, Lou Emil, Muqbil Irfana, Farrell Alex Patrick, Swensen Jeffrey, Oberley Matthew James, Nabhan Chadi, Goel Sanjay, Shields Anthony F, Mohammad Ramzi M, Pasche Boris C, Azmi Asfar S
IHA Hematology Oncology, Pontiac, MI.
Wayne State University, Detroit, MI.
JCO Oncol Adv. 2025 May 2;2(1):e2400032. doi: 10.1200/OA-24-00032. eCollection 2025.
The mammalian target of rapamycin (mTOR) inhibitor everolimus is US Food and Drug Administration-approved for advanced pancreatic neuroendocrine neoplasms (pNENs), yet resistance is common, necessitating the identification of resistance mechanisms for effective treatment strategies. Previous studies suggest that targeting the aberrant expression of mTOR regulators p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) sensitizes pNENs to everolimus. In this study, we queried a large real-world data set of pNENs, characterizing the molecular and immune landscapes, as well as the clinical outcomes associated with aberrant PAK4 and NAMPT expression.
Two-hundred and ninety-four pNEN cases were analyzed using next-generation sequencing and whole-exome/whole-transcriptome sequencing. We stratified patients into clusters on the basis of median cutoff.
High expression of genes activated in response to mTOR activation was found in NAMPT-high and PAK4-high groups. Enrichment of PI3K/AKT/mTOR and glycolysis pathways was observed in these tumors. Higher mutation rates in multiple endocrine neoplasia type 1, alpha thalassemia/mental retardation syndrome X-linked, TSC2, SETD2, and CCNE1 were observed in high NAMPT and PAK4 clusters. Immune analysis revealed enrichment in inflammatory response pathways, IL2/STAT5 signaling, and immune checkpoint genes. Increased neutrophils, natural killer cells, and macrophages were found in PAK4-high/NAMPT-high tumors. Analysis of real-world patient data revealed that high PAK4 ( = .0428) or NAMPT ( = .0002) expression individually correlated with lower overall survival in all neuroendocrine neoplasms (NEN) cohorts, while the combined high expression of both was associated with the worst outcomes ( = .0002). Similar trends were observed in pancreatic NEN cohorts.
Our study demonstrates that PAK4-high/NAMPT-high pNENs are associated with distinct molecular and immune profiles. Further investigation is warranted to determine if dual PAK4 and NAMPT blockade enhances the efficacy of immunotherapeutics.
雷帕霉素哺乳动物靶点（mTOR）抑制剂依维莫司已获美国食品药品监督管理局批准用于晚期胰腺神经内分泌肿瘤（pNENs），但耐药情况常见，因此有必要确定耐药机制以制定有效的治疗策略。先前的研究表明，靶向mTOR调节因子p21激活激酶4（PAK4）和烟酰胺磷酸核糖转移酶（NAMPT）的异常表达可使pNENs对依维莫司敏感。在本研究中，我们查询了一个大型的pNENs真实世界数据集，对其分子和免疫图谱以及与PAK4和NAMPT异常表达相关的临床结果进行了表征。
使用二代测序和全外显子组/全转录组测序对294例pNEN病例进行分析。我们根据中位数临界值将患者分层为不同的簇。
在NAMPT高表达组和PAK4高表达组中发现了对mTOR激活有反应而被激活的基因的高表达。在这些肿瘤中观察到PI3K/AKT/mTOR和糖酵解途径的富集。在高NAMPT和PAK4簇中观察到多发性内分泌肿瘤1型、α地中海贫血/智力发育迟缓综合征X连锁、TSC2、SETD2和CCNE1的突变率更高。免疫分析显示炎症反应途径、IL2/STAT5信号通路和免疫检查点基因富集。在PAK4高表达/NAMPT高表达的肿瘤中发现中性粒细胞、自然杀伤细胞和巨噬细胞增加。对真实世界患者数据的分析显示，在所有神经内分泌肿瘤（NEN）队列中，PAK4高表达（P = 0.0428）或NAMPT高表达（P = 0.0002）分别与较低的总生存期相关，而两者的联合高表达与最差的预后相关（P = 0.0002）。在胰腺NEN队列中观察到类似趋势。
我们的研究表明，PAK4高表达/NAMPT高表达的pNENs与独特的分子和免疫特征相关。有必要进一步研究以确定双重阻断PAK4和NAMPT是否能提高免疫治疗的疗效。
