Netrin1 blockade alleviates resistance to chemotherapy in pancreatic cancer

. 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.

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Journal
Nature
Published
2026-04-22
DOI
https://doi.org/10.1038/s41586-026-10436-4
Primary Topic
Axon Guidance and Neuronal Signaling
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article
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article

Netrin1 blockade alleviates resistance to chemotherapy in pancreatic cancer

Victoire Granger, Édouard Girard, Anthony Turpin, Jean‐Yves Scoazec et al.
Nature
Axon Guidance and Neuronal Signaling
article

Netrin1 blockade alleviates resistance to chemotherapy in pancreatic cancer

Victoire Granger, Édouard Girard, Anthony Turpin, Jean‐Yves Scoazec, Camille Evrard, Pauline Parent, E. Georges, Patrick Mehlen, Jérôme Cros, Jean‐Baptiste Bachet, Thomas Decaens, Nicolas Williet, Astrid Lièvre, Aurélie Durand, O BOUCHE, Nicolas Rama, Jean‐Frédéric Blanc, Julien Ghelfi, Benjamin Ducarouge, Agnès Bernet, Gaël Roth, Mircea Chirica, Christelle d’Engremont, Anna Borowik, Marc Manceau, Eugénie Modolo, Nicolas Braissand, Sébastien Hazard, Matthieu Roustit, Hector Hernandez-Vargas, Pascal Artru
article en

Abstract

. 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.

Nature
Université Claude Bernard Lyon 1 (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Paris Cité (FR), Université de Lille (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Hôpital Beaujon (FR), Centre Hospitalier Universitaire de Grenoble (FR), Centre Hospitalier Universitaire de Lille (FR), CEA Grenoble (FR), Université de Poitiers (FR), Sorbonne Université (FR), Lille’s Cardiology Hospital (FR), Oncogenesis Stress Signaling (FR), Assistance Publique – Hôpitaux de Paris (FR), Netris Pharma (France) (FR), Quantum Genomics (France) (FR), Centre Hospitalier Universitaire de Reims (FR), Centre Hospitalier Universitaire de Poitiers (FR), Institute Cancer De La Loire Lucien Neuwirth (FR), Hôpital Cardiologique du Haut-Lévêque (FR), Pitié-Salpêtrière Hospital (FR), Centre de Recherche en Cancérologie de Lyon (FR), Hôpital Privé Jean Mermo (FR), Grenoble Institute of Neurosciences (FR), Université Grenoble Alpes (FR), Université de Reims Champagne-Ardenne (FR)
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