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A receptor tyrosine kinase ROR1 inhibitor (KAN0439834) induced significant apoptosis of pancreatic cells which was enhanced by erlotinib and ibrutinib
- Source :
- PLoS ONE, Vol 13, Iss 6, p e0198038 (2018), PLoS ONE
- Publication Year :
- 2018
- Publisher :
- Public Library of Science (PLoS), 2018.
-
Abstract
- There is a great unmet medical need in pancreatic carcinoma (PC) for novel drugs with other mechanisms of action than existing. PC cells express the onco-fetal RTK ROR1, absent on most normal post-partem cells. ROR1 is involved in proliferation, survival, EMT and metastasis of tumor cells in various malignancies. A small molecule inhibitor (KAN0439834) (530 Da) targeting the TK domain of ROR1 was developed and the activity in ROR1 expressing human PC cell lines (n = 8) evaluated. The effects were compared to a murine mAb against the external part of ROR1, gemcitabine, erlotinib and ibrutinib. KAN0439834 induced significant apoptosis of the tumor cells. EC50 values for KAN0439834 varied between 250-650 nM depending on the cell line. The corresponding values for erlotinib and ibrutinib were 10-40 folds higher. KAN0439834 was much more effective in inducing tumor cell death than the ROR1 mAb although both inhibited ROR1 phosphorylation and downstream non-canonical Wnt pathway molecules. Combination of KAN0439834 with erlotinib or ibrutinib had significant additive effects on tumor cell death. A first-in-class small molecule ROR1 inhibitor (KAN0439834) showed promising in vitro activity against a number of human PC cell lines. Interesting is the additive effects of erlotinib and ibrutinib which warrants further studies as both these agents are in clinical trials for pancreatic carcinoma.
- Subjects :
- 0301 basic medicine
Cytotoxicity
lcsh:Medicine
Apoptosis
Toxicology
Pathology and Laboratory Medicine
Biochemistry
Receptor tyrosine kinase
Tyrosine Kinases
Lung and Intrathoracic Tumors
chemistry.chemical_compound
0302 clinical medicine
Piperidines
Medicine and Health Sciences
Organic Chemicals
Phosphorylation
Post-Translational Modification
lcsh:Science
Multidisciplinary
biology
Cell Death
Chemistry
Organic Compounds
Wnt signaling pathway
Drug Synergism
Enzymes
Gene Expression Regulation, Neoplastic
Oncology
Cell Processes
030220 oncology & carcinogenesis
Ibrutinib
Low Density Lipoprotein Receptor-Related Protein-6
Physical Sciences
Erlotinib
Tyrosine kinase
medicine.drug
Research Article
Biotechnology
Antineoplastic Agents
Receptor Tyrosine Kinase-like Orphan Receptors
Carcinomas
03 medical and health sciences
Erlotinib Hydrochloride
Pancreatic Cancer
Pancreatic cancer
Cell Line, Tumor
Gastrointestinal Tumors
medicine
Humans
Protein Structure, Quaternary
Pancreas
Protein Kinase Inhibitors
Adenine
Organic Chemistry
lcsh:R
Chemical Compounds
Biology and Life Sciences
Proteins
Cancers and Neoplasms
Cell Biology
medicine.disease
Pancreatic Neoplasms
030104 developmental biology
Pyrimidines
Small Molecules
ROR1
Cancer research
biology.protein
Enzymology
Pyrazoles
lcsh:Q
Protein Multimerization
Protein Kinases
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 13
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....4a4c30a40aef7e4b3a81e9182e386b9e