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Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy
W Leconet1, C Larbouret1, T Chardès1
1INSERM-U896, IRCM, Université Montpellier1, CRLC Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Montpellier-Cedex 5, France.
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.
Insights
Monoclonal antibodies targeting AXL receptor tyrosine kinase (RTK) effectively inhibit pancreatic cancer cell growth and migration. This research shows anti-AXL mAbs offer a promising new immunotherapy for pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- AXL receptor tyrosine kinase (RTK) is a key driver of proliferation and invasion in pancreatic ductal adenocarcinoma (PDAC).
- Effective therapeutic strategies for PDAC are urgently needed, highlighting the importance of targeting key oncogenic pathways.
- AXL expression is prevalent in PDAC, particularly in invasive cell populations, suggesting its critical role in disease progression.
Purpose of the Study:
- To investigate the efficacy of monoclonal antibodies (mAbs) targeting AXL RTK in inhibiting pancreatic cancer cell proliferation and migration.
- To evaluate the therapeutic potential of anti-AXL mAbs as a novel immunotherapy for pancreatic cancer.
Main Methods:
- AXL expression was assessed in PDAC tissues using immunohistochemistry.
- AXL's role in oncogenesis was studied via short hairpin RNA knockdown in pancreatic cancer cell lines.
- In vitro and in vivo studies utilized generated anti-human AXL mAbs to assess their inhibitory effects on pancreatic cancer cell lines and tumor xenografts.
Main Results:
- AXL was expressed in 76% of PDAC samples and localized to invasive cells.
- AXL knockdown reduced pancreatic cancer cell migration, survival, proliferation, and tumor growth in vivo.
- Anti-AXL mAbs (D9 and E8) inhibited AXL phosphorylation, AKT signaling, and suppressed proliferation and migration in vitro and reduced tumor growth in vivo.
Conclusions:
- AXL receptor is a significant therapeutic target in pancreatic cancer.
- Anti-AXL mAbs demonstrate potent anti-tumor activity by inhibiting AXL signaling and inducing receptor internalization.
- Preclinical data strongly support the development of anti-AXL mAbs as a novel immunotherapy for pancreatic cancer.
