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Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells

The receptor tyrosine kinase, anexelekto (Axl) is involved in tumor cell growth, migration and invasion, and has been associated with chemotherapy resistance, which makes it an attractive target for cancer therapy. In total, six Axl-targeted monoclonal antibodies (mAbs) and two antibody-drug conjuga...

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Autores principales: Chang, Hong, An, Ran, Li, Xinying, Lang, Xiaoling, Feng, Jiannan, Lv, Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436363/
https://www.ncbi.nlm.nih.gov/pubmed/34539853
http://dx.doi.org/10.3892/ol.2021.13010
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author Chang, Hong
An, Ran
Li, Xinying
Lang, Xiaoling
Feng, Jiannan
Lv, Ming
author_facet Chang, Hong
An, Ran
Li, Xinying
Lang, Xiaoling
Feng, Jiannan
Lv, Ming
author_sort Chang, Hong
collection PubMed
description The receptor tyrosine kinase, anexelekto (Axl) is involved in tumor cell growth, migration and invasion, and has been associated with chemotherapy resistance, which makes it an attractive target for cancer therapy. In total, six Axl-targeted monoclonal antibodies (mAbs) and two antibody-drug conjugates have been reported in the last 10 years, which have been shown to have bioactivity in inhibiting tumor cell proliferation and migration. The Axl external cell domain (Axl(−ECD)), consisting of 426 amino acids, has always been used as an antigen in the screening process for all six of these Axl-targeted mAbs. However, the Axl functional domain, which interacts with its natural ligand, growth arrest-specific protein 6 (Gas6), is only a small part of the Axl(−ECD). Antibodies targeting the Axl functional domain may efficiently block Gas6-Axl binding and attenuate its downstream signals and activities. To the best of our knowledge, no mAbs targeting the Axl functional domain have been reported. In the present study, a major Axl functional domain interacting with Gas6 was determined using bioinformatics and structural biology methods. In MDA-MB-231 breast cancer cell assays, anti-Axl mAbs targeting this relatively specific Axl functional domain almost completely neutralized the stimulation of Gas6 in both Axl phosphorylation and cell migration assays, and showed similar activity to the positive control drug R428 (a small molecular tyrosine kinase inhibitor of Axl currently in phase II clinical trials) in the cell migration assay. Given the important role of Axl in tumor development and chemotherapy resistance, Axl-targeted mAbs could be used to inhibit tumor cells directly, as well as reduce the development of chemotherapy resistance by blocking Axl activity. The application of Axl-targeted mAbs combined with chemotherapy provides a promising treatment strategy for patients with tumors, particularly those with triple-negative breast cancer, for whom no targeted therapy is currently available.
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spelling pubmed-84363632021-09-17 Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells Chang, Hong An, Ran Li, Xinying Lang, Xiaoling Feng, Jiannan Lv, Ming Oncol Lett Articles The receptor tyrosine kinase, anexelekto (Axl) is involved in tumor cell growth, migration and invasion, and has been associated with chemotherapy resistance, which makes it an attractive target for cancer therapy. In total, six Axl-targeted monoclonal antibodies (mAbs) and two antibody-drug conjugates have been reported in the last 10 years, which have been shown to have bioactivity in inhibiting tumor cell proliferation and migration. The Axl external cell domain (Axl(−ECD)), consisting of 426 amino acids, has always been used as an antigen in the screening process for all six of these Axl-targeted mAbs. However, the Axl functional domain, which interacts with its natural ligand, growth arrest-specific protein 6 (Gas6), is only a small part of the Axl(−ECD). Antibodies targeting the Axl functional domain may efficiently block Gas6-Axl binding and attenuate its downstream signals and activities. To the best of our knowledge, no mAbs targeting the Axl functional domain have been reported. In the present study, a major Axl functional domain interacting with Gas6 was determined using bioinformatics and structural biology methods. In MDA-MB-231 breast cancer cell assays, anti-Axl mAbs targeting this relatively specific Axl functional domain almost completely neutralized the stimulation of Gas6 in both Axl phosphorylation and cell migration assays, and showed similar activity to the positive control drug R428 (a small molecular tyrosine kinase inhibitor of Axl currently in phase II clinical trials) in the cell migration assay. Given the important role of Axl in tumor development and chemotherapy resistance, Axl-targeted mAbs could be used to inhibit tumor cells directly, as well as reduce the development of chemotherapy resistance by blocking Axl activity. The application of Axl-targeted mAbs combined with chemotherapy provides a promising treatment strategy for patients with tumors, particularly those with triple-negative breast cancer, for whom no targeted therapy is currently available. D.A. Spandidos 2021-11 2021-08-27 /pmc/articles/PMC8436363/ /pubmed/34539853 http://dx.doi.org/10.3892/ol.2021.13010 Text en Copyright: © Chang et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Chang, Hong
An, Ran
Li, Xinying
Lang, Xiaoling
Feng, Jiannan
Lv, Ming
Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells
title Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells
title_full Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells
title_fullStr Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells
title_full_unstemmed Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells
title_short Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells
title_sort anti-axl monoclonal antibodies attenuate the migration of mda-mb-231 breast cancer cells
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436363/
https://www.ncbi.nlm.nih.gov/pubmed/34539853
http://dx.doi.org/10.3892/ol.2021.13010
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