Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy.: Anti-AXL mAb for pancreatic cancer immunotherapy

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.Oncogene advance online publication, 18 November 2013; doi:10.1038/onc.2013.487.
Type de document :
Article dans une revue
Oncogene, Nature Publishing Group, 2014, 33 (47), pp.5405-14. 〈10.1038/onc.2013.487〉
Liste complète des métadonnées

http://www.hal.inserm.fr/inserm-00916587
Contributeur : Yves Le Ster <>
Soumis le : vendredi 16 mai 2014 - 16:38:50
Dernière modification le : mercredi 5 septembre 2018 - 11:32:01

Fichiers

Supplementary_information.pdf
Fichiers produits par l'(les) auteur(s)

Identifiants

Citation

Wilhem Leconet, Christel Larbouret, Thierry Chardès, Gaëlle Thomas, Madeline Neiveyans, et al.. Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy.: Anti-AXL mAb for pancreatic cancer immunotherapy. Oncogene, Nature Publishing Group, 2014, 33 (47), pp.5405-14. 〈10.1038/onc.2013.487〉. 〈inserm-00916587〉

Partager

Métriques

Consultations de la notice

910

Téléchargements de fichiers

1116