1. Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia
2. Commonwealth Scientific and Industrial Research Organisation, Herston, QLD, Australia
3. China Medical University, Shenyang, China
4. Preclinical Imaging Facility, Translational Research Institute, Woolloongabba, QLD, Australia
5. Mater Health Services, South Brisbane, QLD, Australia
6. The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, Sydney, NSW, Australia
7. St Vincent's Clinical School, Faculty of Medicine, University of NSW Sydney, NSW, Australia
8. The Scripps Research Institute, La Jolla, CA, USA
9. Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
10. Faculty of Medicine, The University of Queensland, St. Lucia, QLD, Australia
11. Redcliffe Hospital, Metro North Hospital and Health Service, Brisbane, QLD, Australia
12. Upper Gastrointestinal/Soft Tissue Unit, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
13. Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia
14. Royal Brisbane and Women's Hospital, Herston, QLD, Australia
15. Herston Imaging Research Facility, Herston, QLD, Australia
Background: CUB domain-containing protein 1 (CDCP1) is a cell surface receptor regulating key signalling pathways in malignant cells. CDCP1 has been proposed as a molecular target to abrogate oncogenic signalling pathways and specifically deliver anti-cancer agents to tumors. However, the development of CDCP1-targeting agents has been questioned by its frequent proteolytic processing which was thought to result in shedding of the CDCP1 extracellular domain limiting its targetability. In this study, we investigated the relevance of targeting CDCP1 in the context of pancreatic ductal adenocarcinoma (PDAC) and assess the impact of CDCP1 proteolysis on the effectiveness of CDCP1 targeting agents.
Methods: The involvement of CDCP1 in PDAC progression was assessed by association analysis in several PDAC cohorts and the proteolytic processing of CDCP1 was evaluated in PDAC cell lines and patient-derived cells. The consequences of CDCP1 proteolysis on its targetability in PDAC cells was assessed using immunoprecipitation, immunostaining and biochemical assays. The involvement of CDCP1 in PDAC progression was examined by loss-of-function in vitro and in vivo experiments employing PDAC cells expressing intact or cleaved CDCP1. Finally, we generated antibody-based imaging and therapeutic agents targeting CDCP1 to demonstrate the feasibility of targeting this receptor for detection and treatment of PDAC tumors.
Results: High CDCP1 expression in PDAC is significantly associated with poorer patient survival. In PDAC cells proteolysis of CDCP1 does not always result in the shedding of CDCP1-extracellular domain which can interact with membrane-bound CDCP1 allowing signal transduction between the different CDCP1-fragments. Targeting CDCP1 impairs PDAC cell functions and PDAC tumor growth independently of CDCP1 cleavage status. A CDCP1-targeting antibody is highly effective at delivering imaging radionuclides and cytotoxins to PDAC cells allowing specific detection of tumors by PET/CT imaging and superior anti-tumor effects compared to gemcitabine in in vivo models.
Conclusion: Independent of its cleavage status, CDCP1 exerts oncogenic functions in PDAC and has significant potential to be targeted for improved radiological staging and treatment of this cancer. Its elevated expression by most PDAC tumors and lack of expression by normal pancreas and other major organs, suggest that targeting CDCP1 could benefit a significant proportion of PDAC patients. These data support the further development of CDCP1-targeting agents as personalizable tools for effective imaging and treatment of PDAC.
Keywords: pancreatic cancer, theranostics, monoclonal-antibody, PET-CT, CDCP1