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Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy

Oncogene volume 33, pages 5405–5414 (2014)Cite this article

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Abstract

AXL receptor tyrosine kinase (RTK) is implicated in proliferation and invasion of many cancers, particularly in pancreatic ductal adenocarcinoma (PDAC), for which new therapeutic options are urgently required. We investigated whether inhibition of AXL activity by specific monoclonal antibodies (mAbs) is efficient in limiting proliferation and migration of pancreatic cancer cells. Expression of AXL was evaluated by immunohistochemistry in 42 PDAC. The AXL role in oncogenesis was studied using the short hairpin RNA approach in a pancreatic carcinoma cell line. We further generated antihuman AXL mAbs and evaluated their inhibitory effects and the AXL downstream signaling pathways first in vitro, in a panel of pancreatic cancer cell lines and then in vivo, using subcutaneous or orthotopic pancreatic tumor xenografts. AXL receptor was found expressed in 76% (32/42) of PDAC and was predominantly present in invasive cells. The AXL-knockdown Panc-1 cells decreased in vitro cell migration, survival and proliferation, and reduced in vivo tumor growth. Two selected anti-AXL mAbs (D9 and E8), which inhibited phosphorylation of AXL and of its downstream target AKT without affecting growth arrest-specific factor 6 (GAS6) binding, induced downexpression of AXL by internalization, leading to an inhibition of proliferation and migration in the four pancreatic cancer cell lines studied. In vivo, treatment by anti-AXL mAbs significantly reduced growth of both subcutaneous and orthotopic pancreatic tumor xenografts independently of their KRAS mutation status. Our in vitro and preclinical in vivo data demonstrate that anti-human AXL mAbs could represent a new approach to the pancreatic cancer immunotherapy.

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Acknowledgements

We thank Florence Frayssinoux, Sabine Bousquié and Geneviève Heintz for their technical help. We also thank the ICRM animal facility staff and the ‘Réseau d’Histologie Expérimentale de Montpellier’ histology facility for processing our animal tissues and RIO Imaging facilities. This work was supported by INSERM and Oribase Pharma.

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Authors and Affiliations

  1. INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France

    W Leconet, C Larbouret, T Chardès, G Thomas, M Neiveyans, M Busson, M Pugnière, F Bernex, A Pèlegrin & B Robert

  2. Unité de Biostatistiques, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France

    M Jarlier

  3. Département de biopathologie Centre Jean-Perrin 63011 Clermont-Ferrand Cedex 1; ERTICa EA4677, Université d'Auvergne,

    N Radosevic-Robin & F Penault-Llorca

  4. ERTICa EA4677, Université d'Auvergne, Clermont-Ferrand, France

    N Radosevic-Robin & F Penault-Llorca

  5. INSERM-U876, Hématopoïèse Leucémique et Cible Thérapeutique, Université Victor Ségalen, Laboratoire d'hématologie CHU de Bordeaux, Bordeaux Cedex, France

    J-M Pasquet

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  1. W Leconet
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Correspondence to B Robert.

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Competing interests

Wilhem Leconet, Christel Larbouret, Thierry Chardes, André Pèlegrin and Bruno Robert are inventors on anti-AXL mAb patents related to this work. The other authors declare no conflict of interest.

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Leconet, W., Larbouret, C., Chardès, T. et al. Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy. Oncogene 33, 5405–5414 (2014). https://doi.org/10.1038/onc.2013.487

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