A receptor tyrosine kinase ROR1 inhibitor (KAN0439834) induced significant apoptosis of pancreatic cells which was enhanced by erlotinib and ibrutinib.

Autor: Daneshmanesh AH; Department of Oncology-Pathology, Immune and Gene therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna, Stockholm, Sweden.; Karolinska Institutet, Stockholm, Sweden., Hojjat-Farsangi M; Department of Oncology-Pathology, Immune and Gene therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna, Stockholm, Sweden.; Karolinska Institutet, Stockholm, Sweden., Ghaderi A; Department of Oncology-Pathology, Immune and Gene therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna, Stockholm, Sweden.; Karolinska Institutet, Stockholm, Sweden., Moshfegh A; Department of Oncology-Pathology, Immune and Gene therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna, Stockholm, Sweden.; Karolinska Institutet, Stockholm, Sweden., Hansson L; Department of Oncology-Pathology, Immune and Gene therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna, Stockholm, Sweden.; Karolinska Institutet, Stockholm, Sweden.; Department of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden., Schultz J; Kancera AB, Karolinska Institutet Science Park, Stockholm, Sweden., Vågberg J; Kancera AB, Karolinska Institutet Science Park, Stockholm, Sweden., Byström S; Kancera AB, Karolinska Institutet Science Park, Stockholm, Sweden., Olsson E; Kancera AB, Karolinska Institutet Science Park, Stockholm, Sweden., Olin T; Kancera AB, Karolinska Institutet Science Park, Stockholm, Sweden., Österborg A; Department of Oncology-Pathology, Immune and Gene therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna, Stockholm, Sweden.; Karolinska Institutet, Stockholm, Sweden.; Department of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden., Mellstedt H; Department of Oncology-Pathology, Immune and Gene therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna, Stockholm, Sweden.; Karolinska Institutet, Stockholm, Sweden.; Department of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2018 Jun 01; Vol. 13 (6), pp. e0198038. Date of Electronic Publication: 2018 Jun 01 (Print Publication: 2018).
DOI: 10.1371/journal.pone.0198038
Abstrakt: 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.
Competing Interests: AHD, MHF, AM, JS, JV, SB, EO, TO, AÖ and HM are shareholders of Kancera AB. AM, JS, JV, SB, EO, and TO are employees of Kancera AB. HM has received research grants from Kancera. Kancera AB did not have any role in the study design, data collection, analyses, decision to publish. The specific roles of the authors are articulated in the Author Contributions section. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
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