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Translational Therapeutics

ATR inhibition potentiates FOLFIRINOX cytotoxic effect in models of pancreatic ductal adenocarcinoma by remodelling the tumour microenvironment

British Journal of Cancer volume 132, pages 222–235 (2025)Cite this article

Subjects

Abstract

Background

In pancreatic ductal adenocarcinoma (PDAC), the dense stroma rich in cancer-associated fibroblasts (CAFs) and the immunosuppressive microenvironment confer resistance to treatments. To overcome such resistance, we tested the combination of FOLFIRINOX (DNA damage-inducing chemotherapy drugs) with VE-822 (an ataxia-telangiectasia and RAD3-related inhibitor that targets DNA damage repair).

Methods

PDAC spheroid models and organoids were used to assess the combination effects. Tumour growth and the immune and fibrotic microenvironment were evaluated by immunohistochemistry, single-cell analysis and spatial proteomics in patient-derived xenograft (PDX) and orthotopic immunocompetent KPC mouse models.

Results

The FOLFIRINOX and VE-822 combination had a strong synergistic effect in several PDAC cell lines, whatever their BRCA1, BRCA2 and ATM mutation status and resistance to standard chemotherapy agents. This was associated with high DNA damage and inhibition of DNA repair signalling pathways, leading to increased apoptosis. In immunocompetent and PDX mouse models of PDAC, the combination inhibited tumour growth more effectively than FOLFIRINOX alone. This was associated with tumour microenvironment remodelling, particularly decreased proportion of fibroblast activated protein-positive CAFs and increased anti-tumorigenic immune cell infiltration and interaction.

Conclusion

The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC.

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Fig. 1: The combination of an ATR inhibitor with FOLFIRINOX affects pancreatic cancer cell viability in vitro.
Fig. 2: The VE-822 and FOLFIRINOX combination induces PDAC cell death and a cytostatic effect in CAFs in 2D and 3D co-culture models.
Fig. 3: The VE-822 and FOLFIRINOX combination induces DNA damage and inhibits DNA damage repair pathways.
Fig. 4: The VE-822 and FOLFIRINOX combination inhibits tumour growth in several immunodeficient mouse models and remodulates the tumour microenvironment.
Fig. 5: The VE-822 and FOLFIRINOX combination inhibits tumour growth in an immunocompetent mouse model by increasing immune cell infiltration.
Fig. 6: The VE-822 and FOLFIRINOX combination induces a remodelling of the tumour microenvironment.

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Data availability

All materials and data described in the manuscript are available to any researcher wishing to use them for non-commercial purposes.

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Acknowledgements

The staff at the IRCM animal facility, the PDX and MRI platforms, are greatly acknowledged. We acknowledge the 'Réseau d’Histologie Expérimentale de Montpellier'—RHEM facility supported by SIRIC Montpellier Cancer (Grant INCa_Inserm_DGOS_12553), the European Regional Development Foundation and the Occitanie region (FEDER-FSE 2014-2020 Languedoc Roussillon) for processing our animal tissues, histology techniques and expertise. Daniel Vezzio and André Pèlegrin are also acknowledged for their financial support. All the methods and experimental protocols done on live vertebrates were done in accordance with the French regulations and ethical guidelines for experimental animal studies in an accredited establishment (Agreement No. E34-172-27, NFX50-900 certification).

Funding

This work was supported by grants from the Ligue Nationale Contre le Cancer, Comité de l’Hérault, the Gefluc and by the French National Research Agency (ANR) under the Programme Investissement d’Avenir (grant agreement: Labex MabImprove, ANR-10-LABX-53-01).

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Author notes

  1. These authors contributed equally: Véronique Garambois, Nadia Vie, Céline Gongora, Christel Larbouret.

Authors and Affiliations

  1. IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France

    Marine Bruciamacchie, Véronique Garambois, Nadia Vie, Thomas Bessede, Henri-Alexandre Michaud, Laure-Agnès Chepeaux, Laurent Gros, Nathalie Bonnefoy, Mathilde Robin, Dorian Brager, Kevin Bigot, Philippe Pourquier, Jacques Colinge, Pierre-Emmanuel Colombo, Marta Jarlier, Diégo Tosi & Christel Larbouret

  2. IRCM, Univ Montpellier, Inserm, ICM, CHU Nimes, Montpellier, France

    Alexandre Evrard

  3. INSERM UMLR-1308, University of Limoges, Limoges, France

    Muriel Mathonnet

  4. Université Toulouse III-Paul Sabatier—Centre de Recherche en Cancérologie de Toulouse (CRCT)—UMR1037 Inserm– UMR 5071 CNRS, Toulouse, France

    Ismahane Belhabib, Christine Jean & Corinne Bousquet

  5. IRCM, Univ Montpellier, Inserm, ICM, CNRS, Montpellier, France

    Céline Gongora

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  1. Marine Bruciamacchie
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Contributions

MB, VG, NV, HAM, LG, DB, KB, TB, AE, CJ, IB: collected the data and performed the analysis, LAC, MR, MJ, JC: contributed to informatic analysis tools, MM, PEC, CB: contributed to the collection of the cell lines and samples, VG, NV, DT, NB, CL and CG: contributed to the design of the experiments, VG and MB: contributed to mice experiment, CL and CG conceived, designed the experiments and analyses, MB, NB, PP, CG and CL wrote the paper.

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Correspondence to Christel Larbouret.

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Bruciamacchie, M., Garambois, V., Vie, N. et al. ATR inhibition potentiates FOLFIRINOX cytotoxic effect in models of pancreatic ductal adenocarcinoma by remodelling the tumour microenvironment. Br J Cancer 132, 222–235 (2025). https://doi.org/10.1038/s41416-024-02904-3

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