近日，法国里昂大学Patrick Mehlen及其团队的最新研究揭示了Netrin1阻断剂减轻胰腺癌化疗耐药。2026年4月22日出版的《自然》发表了这项成果。

在此，该团队报告了一项1b期研究的结果，该研究评估了NP137与改良的FOLFIRINOX （mFOLFIRINOX）联合治疗一线局部晚期胰腺癌患者（ClinicalTrials.gov: NCT05546853）。43名患者入组，每隔一周接受mFOLFIRINOX plthem NP137治疗，共12个周期。NP137耐受性良好。中位无进展生存期（PFS）为10.85个月（95%可信区间，10.03-15.61），中位总生存期为16.43个月（95%可信区间，12.75 -未达到），截止数据时有21例患者仍然存活。23%的患者进行了治疗后转换手术。对治疗前活检和手术标本进行激光捕获显微解剖。微体RNA测序证实mFOLFIRINOX与NP137联合下调的主要途径是EMT。

此外，肿瘤细胞中negenin-1受体表达水平高的患者的生存期延长- negenin -高组中位PFS为15.65个月，neogenin低组中位PFS为10.22个月。他们的研究结果支持了netrin1阻断剂通过抑制EMT来减轻化疗耐药性的观点，特别是在neogenin含量高的胰腺癌中。

据介绍，Netrin1是一种发育线索，是肿瘤上皮-间质转化（EMT）的主要调节因子，EMT是一种已知的驱动化疗耐药性的机制。一种netrin1抗体（NP137）已被证明在临床前和临床环境中抑制肿瘤的EMT。在胰腺癌动物模型中，netrin1及其受体neogenin已被证明可促进肿瘤进展、EMT5和转移。

附：英文原文

Title: Netrin1 blockade alleviates resistance to chemotherapy in pancreatic cancer

Author: Roth, Gael, Artru, Pascal, Bouche, Olivier, Williet, Nicolas, Ghelfi, Julien, Turpin, Anthony, Lievre, Astrid, Blanc, Jean-Frdric, Evrard, Camille, Bachet, Jean-Baptiste, Parent, Pauline, Manceau, Marc, Roustit, Matthieu, Borowik, Anna, Granger, Victoire, Durand, Aurlie, dEngremont, Christelle, Girard, Edouard, Chirica, Mircea, Braissand, Nicolas, Rama, Nicolas, Modolo, Eugnie, Hernandez-Vargas, Hector, Georges, Elise, Scoazec, Jean-Yves, Cros, Jerome, Hazard, Sbastien, Ducarouge, Benjamin, Decaens, Thomas, Bernet, Agns, Mehlen, Patrick

Issue&Volume: 2026-04-22

Abstract: Netrin1, a developmental cue, is a master regulator of tumour epithelial-to-mesenchymal transition (EMT)1, a mechanism that is known to drive resistance to chemotherapy2. A netrin1 antibody (NP137)3 has been shown to inhibit tumour EMT in preclinical1 and clinical4 settings. In animal models of pancreatic cancer, netrin1 and its receptor neogenin have been shown to promote tumour progression5, EMT5 and metastasis6. Here we report the results of a phase 1b study that assesses the combination of NP137 with modified FOLFIRINOX (mFOLFIRINOX) in first line patients with locally advanced pancreatic cancer (ClinicalTrials.gov: NCT05546853). Forty-three patients were enrolled and received mFOLFIRINOX plus NP137 every other week for up to 12 cycles. NP137 was well tolerated. Median progression-free survival (PFS) was 10.85 months (95% confidence interval, 10.03–15.61) and median overall survival was 16.43 months (95% confidence interval, 12.75–non-reached), with 21 patients remaining alive at the time of data cut-off. Post-therapy conversion surgery occurred in 23% of patients. Laser capture microdissection was performed on pre-therapeutic biopsies and surgical specimens. Microbulk RNA sequencing confirmed that the main pathway that was down-regulated with the combination of mFOLFIRINOX plus NP137 was EMT. Moreover, survival outcomes were extended for patients with tumour cells that expressed high levels of the netrin1 receptor neogenin—median PFS 15.65 months in neogenin-high versus 10.22 months in neogenin low. Our results support the idea that netrin1 blockade alleviates resistance to chemotherapy by inhibiting EMT, particularly in neogenin-high pancreatic cancer.

DOI: 10.1038/s41586-026-10436-4

Source: https://www.nature.com/articles/s41586-026-10436-4