ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells
Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institutet, 17164 Stockholm, Sweden
Kancera AB, Karolinska Institute Science Park, 171 48 Solna, Sweden
Department of Immunology, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, 171 76 Stockholm, Sweden
Department of Hematology, Karolinska University Hospital Solna, 171 77 Stockholm, Sweden
Department of Pathology, Medical School, University of Crete, 71110 Heraklion Crete, Greece
Author to whom correspondence should be addressed.
Biomedicines 2020, 8(6), 170; https://doi.org/10.3390/biomedicines8060170
Received: 14 May 2020 / Revised: 10 June 2020 / Accepted: 19 June 2020 / Published: 23 June 2020
(This article belongs to the Section Cancer Therapeutics)
The receptor tyrosine kinase ROR1 is absent in most normal adult tissues, but overexpressed in several malignancies. In this study, we explored clinical and functional inhibitory aspects of ROR1 in diffuse large B-cell lymphoma (DLBCL). ROR1 expression in tumor cells was more often observed in primary refractory DLBCL, Richter’s syndrome and transformed follicular lymphoma than in relapsed and non-relapsed DLBCL patients (p < 0.001). A survival effect of ROR1 expression was preliminarily observed in relapsed/refractory patients independent of gender and stage but not of age, cell of origin and international prognostic index. A second generation small molecule ROR1 inhibitor (KAN0441571C) induced apoptosis of ROR1+ DLBCL cell lines, similar to venetoclax (BCL-2 inhibitor) but superior to ibrutinib (BTK inhibitor). The combination of KAN0441571C and venetoclax at EC50 concentrations induced almost complete killing of DLBCL cell lines. Apoptosis was accompanied by the downregulation of BCL-2 and MCL-1 and confirmed by the cleavage of PARP and caspases 3, 8, 9. PI3Kδ/AKT/mTOR (non-canonical Wnt pathway) as well as β-catenin and CK1δ (canonical pathway) were inactivated. In zebra fishes transplanted with a ROR1+ DLBCL cell line, KAN0441571C induced a significant tumor reduction. New drugs with mechanisms of action other than those available for DLBCL are warranted. ROR1 inhibitors might represent a novel promising approach.