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ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells

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 prima...

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Autores principales: Ghaderi, Amineh, Daneshmanesh, Amir Hossein, Moshfegh, Ali, Kokhaei, Parviz, Vågberg, Jan, Schultz, Johan, Olin, Thomas, Harrysson, Sara, Smedby, Karin E, Drakos, Elias, Rassidakis, Georgios Z., Österborg, Anders, Mellstedt, Håkan, Hojjat-Farsangi, Mohammad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344684/
https://www.ncbi.nlm.nih.gov/pubmed/32586008
http://dx.doi.org/10.3390/biomedicines8060170
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author Ghaderi, Amineh
Daneshmanesh, Amir Hossein
Moshfegh, Ali
Kokhaei, Parviz
Vågberg, Jan
Schultz, Johan
Olin, Thomas
Harrysson, Sara
Smedby, Karin E
Drakos, Elias
Rassidakis, Georgios Z.
Österborg, Anders
Mellstedt, Håkan
Hojjat-Farsangi, Mohammad
author_facet Ghaderi, Amineh
Daneshmanesh, Amir Hossein
Moshfegh, Ali
Kokhaei, Parviz
Vågberg, Jan
Schultz, Johan
Olin, Thomas
Harrysson, Sara
Smedby, Karin E
Drakos, Elias
Rassidakis, Georgios Z.
Österborg, Anders
Mellstedt, Håkan
Hojjat-Farsangi, Mohammad
author_sort Ghaderi, Amineh
collection PubMed
description 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 EC(50) 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.
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spelling pubmed-73446842020-07-09 ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells Ghaderi, Amineh Daneshmanesh, Amir Hossein Moshfegh, Ali Kokhaei, Parviz Vågberg, Jan Schultz, Johan Olin, Thomas Harrysson, Sara Smedby, Karin E Drakos, Elias Rassidakis, Georgios Z. Österborg, Anders Mellstedt, Håkan Hojjat-Farsangi, Mohammad Biomedicines Article 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 EC(50) 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. MDPI 2020-06-23 /pmc/articles/PMC7344684/ /pubmed/32586008 http://dx.doi.org/10.3390/biomedicines8060170 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ghaderi, Amineh
Daneshmanesh, Amir Hossein
Moshfegh, Ali
Kokhaei, Parviz
Vågberg, Jan
Schultz, Johan
Olin, Thomas
Harrysson, Sara
Smedby, Karin E
Drakos, Elias
Rassidakis, Georgios Z.
Österborg, Anders
Mellstedt, Håkan
Hojjat-Farsangi, Mohammad
ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells
title ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells
title_full ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells
title_fullStr ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells
title_full_unstemmed ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells
title_short ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells
title_sort ror1 is expressed in diffuse large b-cell lymphoma (dlbcl) and a small molecule inhibitor of ror1 (kan0441571c) induced apoptosis of lymphoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344684/
https://www.ncbi.nlm.nih.gov/pubmed/32586008
http://dx.doi.org/10.3390/biomedicines8060170
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