Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy.
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.
INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
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Leconet
INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
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Larbouret
INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
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Chardès
INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
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Thomas
INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
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Neiveyans
INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
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Busson
Unité de Biostatistiques, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
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Jarlier
Département de biopathologie Centre Jean-Perrin 63011 Clermont-Ferrand Cedex 1; ERTICa EA4677, Université d'Auvergne, Clermont-Ferrand, France.
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Radosevic-Robin
INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
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Pugnière
INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
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Bernex
Département de biopathologie Centre Jean-Perrin 63011 Clermont-Ferrand Cedex 1; ERTICa EA4677, Université d'Auvergne, Clermont-Ferrand, France.
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Penault-Llorca
INSERM-U876, Hématopoïèse Leucémique et Cible Thérapeutique, Université Victor Ségalen, Laboratoire d'hématologie CHU de Bordeaux, Bordeaux Cedex, France.
J-M
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Pasquet
INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
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Pèlegrin
INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
B
B
Robert
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D000911:Antibodies, Monoclonal; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases; D018631:ras Proteins; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C117307:KRAS protein, human