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A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells
The ROR1 receptor tyrosine kinase is expressed in embryonic tissues but is absent in normal adult tissues. ROR1 is of importance in oncogenesis and is overexpressed in several cancers, such as NSCLC. In this study, we evaluated ROR1 expression in NSCLC patients (N = 287) and the cytotoxic effects of...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10145660/ https://www.ncbi.nlm.nih.gov/pubmed/37111634 http://dx.doi.org/10.3390/pharmaceutics15041148 |
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author | Ghaderi, Amineh Okhovat, Mohammad-Ali Lehto, Jemina De Petris, Luigi Manouchehri Doulabi, Ehsan Kokhaei, Parviz Zhong, Wen Rassidakis, Georgios Z. Drakos, Elias Moshfegh, Ali Schultz, Johan Olin, Thomas Österborg, Anders Mellstedt, Håkan Hojjat-Farsangi, Mohammad |
author_facet | Ghaderi, Amineh Okhovat, Mohammad-Ali Lehto, Jemina De Petris, Luigi Manouchehri Doulabi, Ehsan Kokhaei, Parviz Zhong, Wen Rassidakis, Georgios Z. Drakos, Elias Moshfegh, Ali Schultz, Johan Olin, Thomas Österborg, Anders Mellstedt, Håkan Hojjat-Farsangi, Mohammad |
author_sort | Ghaderi, Amineh |
collection | PubMed |
description | The ROR1 receptor tyrosine kinase is expressed in embryonic tissues but is absent in normal adult tissues. ROR1 is of importance in oncogenesis and is overexpressed in several cancers, such as NSCLC. In this study, we evaluated ROR1 expression in NSCLC patients (N = 287) and the cytotoxic effects of a small molecule ROR1 inhibitor (KAN0441571C) in NSCLC cell lines. ROR1 expression in tumor cells was more frequent in non-squamous (87%) than in squamous (57%) carcinomas patients, while 21% of neuroendocrine tumors expressed ROR1 (p = 0.0001). A significantly higher proportion of p53 negative patients in the ROR1(+) group than in the p53 positive non-squamous NSCLC patients (p = 0.03) was noted. KAN0441571C dephosphorylated ROR1 and induced apoptosis (Annexin V/PI) in a time- and dose-dependent manner in five ROR1(+) NSCLC cell lines and was superior compared to erlotinib (EGFR inhibitor). Apoptosis was confirmed by the downregulation of MCL-1 and BCL-2, as well as PARP and caspase 3 cleavage. The non-canonical Wnt pathway was involved. The combination of KAN0441571C and erlotinib showed a synergistic apoptotic effect. KAN0441571C also inhibited proliferative (cell cycle analyses, colony formation assay) and migratory (scratch wound healing assay) functions. Targeting NSCLC cells by a combination of ROR1 and EGFR inhibitors may represent a novel promising approach for the treatment of NSCLC patients. |
format | Online Article Text |
id | pubmed-10145660 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-101456602023-04-29 A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells Ghaderi, Amineh Okhovat, Mohammad-Ali Lehto, Jemina De Petris, Luigi Manouchehri Doulabi, Ehsan Kokhaei, Parviz Zhong, Wen Rassidakis, Georgios Z. Drakos, Elias Moshfegh, Ali Schultz, Johan Olin, Thomas Österborg, Anders Mellstedt, Håkan Hojjat-Farsangi, Mohammad Pharmaceutics Article The ROR1 receptor tyrosine kinase is expressed in embryonic tissues but is absent in normal adult tissues. ROR1 is of importance in oncogenesis and is overexpressed in several cancers, such as NSCLC. In this study, we evaluated ROR1 expression in NSCLC patients (N = 287) and the cytotoxic effects of a small molecule ROR1 inhibitor (KAN0441571C) in NSCLC cell lines. ROR1 expression in tumor cells was more frequent in non-squamous (87%) than in squamous (57%) carcinomas patients, while 21% of neuroendocrine tumors expressed ROR1 (p = 0.0001). A significantly higher proportion of p53 negative patients in the ROR1(+) group than in the p53 positive non-squamous NSCLC patients (p = 0.03) was noted. KAN0441571C dephosphorylated ROR1 and induced apoptosis (Annexin V/PI) in a time- and dose-dependent manner in five ROR1(+) NSCLC cell lines and was superior compared to erlotinib (EGFR inhibitor). Apoptosis was confirmed by the downregulation of MCL-1 and BCL-2, as well as PARP and caspase 3 cleavage. The non-canonical Wnt pathway was involved. The combination of KAN0441571C and erlotinib showed a synergistic apoptotic effect. KAN0441571C also inhibited proliferative (cell cycle analyses, colony formation assay) and migratory (scratch wound healing assay) functions. Targeting NSCLC cells by a combination of ROR1 and EGFR inhibitors may represent a novel promising approach for the treatment of NSCLC patients. MDPI 2023-04-05 /pmc/articles/PMC10145660/ /pubmed/37111634 http://dx.doi.org/10.3390/pharmaceutics15041148 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ghaderi, Amineh Okhovat, Mohammad-Ali Lehto, Jemina De Petris, Luigi Manouchehri Doulabi, Ehsan Kokhaei, Parviz Zhong, Wen Rassidakis, Georgios Z. Drakos, Elias Moshfegh, Ali Schultz, Johan Olin, Thomas Österborg, Anders Mellstedt, Håkan Hojjat-Farsangi, Mohammad A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells |
title | A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells |
title_full | A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells |
title_fullStr | A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells |
title_full_unstemmed | A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells |
title_short | A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells |
title_sort | small molecule targeting the intracellular tyrosine kinase domain of ror1 (kan0441571c) induced significant apoptosis of non-small cell lung cancer (nsclc) cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10145660/ https://www.ncbi.nlm.nih.gov/pubmed/37111634 http://dx.doi.org/10.3390/pharmaceutics15041148 |
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