Background/Objectives: Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide, with its incidence rising each year. Despite its relatively low incidence, the aggressiveness of pancreatic cancer results in high mortality, with only 12% of patients surviving five years post-diagnosis. Surgical resection remains the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage. The goal of this work is to identify vulnerabilities that can affect the efficacy of treatments and improve the efficacy of therapy.Methods: MAP17 overexpression in pancreatic cancer cell lines, RT-qPCR analysis, xenografts, in vitro and in vivo treatments, analysis of data from pancreatic tumors in transcriptomic patient databases.Results: We studied the prognostic and predictive value of MAP17 (PDZK1IP1) expression in pancreatic cancer, and we found that high MAP17 mRNA expression was associated with poor prognosis. In addition, single-cell analysis revealed that high MAP17 expression was present only in tumor cells. We investigated whether the response to various antitumor agents depended on MAP17 expression. In 2D culture, MAP17-expressing pancreatic cancer cells responded better to gemcitabine and 5-fluorouracil. However, in vivo xenograft tumors with MAP17 expression showed resistance to all treatments. Additionally, MAP17-expressing cells had a high NAD pool, which seems to be effectively depleted in vivo by NAMPT inhibitors, the primary enzyme for NAD biosynthesis.Conclusions: Our findings suggest that MAP17 expression could enhance the prognostic stratification of pancreatic cancer patients. Moreover, the coadministration of NAMPT inhibitors with current treatments may sensitize tumors with high MAP17 expression to chemotherapy and improve the efficacy of chemotherapy.
背景/目的：胰腺癌是全球癌症相关死亡的第七大原因，其发病率逐年上升。尽管发病率相对较低，但胰腺癌的侵袭性导致其死亡率居高不下，仅12%的患者在确诊后能存活五年。手术切除仍是唯一可能根治的治疗手段，但该肿瘤常在晚期才被确诊。本研究旨在识别可能影响治疗效果的关键薄弱环节，以提升治疗效能。 方法：通过胰腺癌细胞系中MAP17过表达、RT-qPCR分析、异种移植模型、体外与体内治疗实验，并结合转录组患者数据库中胰腺肿瘤数据的综合分析。 结果：我们研究了MAP17（PDZK1IP1）在胰腺癌中的预后与预测价值，发现高MAP17 mRNA表达与不良预后相关。单细胞分析进一步揭示，高MAP17表达仅存在于肿瘤细胞中。通过探究不同抗肿瘤药物的疗效与MAP17表达的关系，发现在二维培养条件下，表达MAP17的胰腺癌细胞对吉西他滨和5-氟尿嘧啶更敏感；然而在体内异种移植模型中，表达MAP17的肿瘤却对所有治疗均表现出耐药性。此外，MAP17高表达细胞具有较高的NAD库容，而NAMPT抑制剂（NAD生物合成的关键酶）在体内能有效耗竭该库容。 结论：本研究提示MAP17表达可优化胰腺癌患者的预后分层。联合使用NAMPT抑制剂与现有化疗方案，可能使高表达MAP17的肿瘤对化疗重获敏感性，从而提升治疗效果。
Efficacy of NAMPT Inhibitors in Pancreatic Cancer After Stratification by MAP17 (PDZK1IP1) Levels
肿瘤(癌症)患者之家