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AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has been a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. AXL has been reported to mediate EGFR-TKIs. Recently, third generation EGFR-TKI osimertinib has been approved and...

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Autores principales: Kim, Donghwa, Bach, Duc-Hiep, Fan, Yan-Hua, Luu, Thi-Thu-Trang, Hong, Ji-Young, Park, Hyen Joo, Lee, Sang Kook
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494839/
https://www.ncbi.nlm.nih.gov/pubmed/31043587
http://dx.doi.org/10.1038/s41419-019-1601-6
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author Kim, Donghwa
Bach, Duc-Hiep
Fan, Yan-Hua
Luu, Thi-Thu-Trang
Hong, Ji-Young
Park, Hyen Joo
Lee, Sang Kook
author_facet Kim, Donghwa
Bach, Duc-Hiep
Fan, Yan-Hua
Luu, Thi-Thu-Trang
Hong, Ji-Young
Park, Hyen Joo
Lee, Sang Kook
author_sort Kim, Donghwa
collection PubMed
description Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has been a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. AXL has been reported to mediate EGFR-TKIs. Recently, third generation EGFR-TKI osimertinib has been approved and yet its acquired resistance mechanism is not clearly understood. We found that AXL is involved in both gefitinib and osimertinib resistance using in vitro and in vivo model. In addition, AXL overexpression was correlated with extended protein degradation rate. We demonstrate targeting AXL degradation is an alternative route to restore EGFR-TKIs sensitivity. We confirmed that the combination effect of YD, an AXL degrader, and EGFR-TKIs can delay or overcome EGFR-TKIs-driven resistance in EGFR-mutant NSCLC cells, xenograft tumors, and patient-derived xenograft (PDX) models. Therefore, combination of EGFR-TKI and AXL degrader is a potentially effective treatment strategy for overcoming and delaying acquired resistance in NSCLC.
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spelling pubmed-64948392019-05-02 AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells Kim, Donghwa Bach, Duc-Hiep Fan, Yan-Hua Luu, Thi-Thu-Trang Hong, Ji-Young Park, Hyen Joo Lee, Sang Kook Cell Death Dis Article Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has been a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. AXL has been reported to mediate EGFR-TKIs. Recently, third generation EGFR-TKI osimertinib has been approved and yet its acquired resistance mechanism is not clearly understood. We found that AXL is involved in both gefitinib and osimertinib resistance using in vitro and in vivo model. In addition, AXL overexpression was correlated with extended protein degradation rate. We demonstrate targeting AXL degradation is an alternative route to restore EGFR-TKIs sensitivity. We confirmed that the combination effect of YD, an AXL degrader, and EGFR-TKIs can delay or overcome EGFR-TKIs-driven resistance in EGFR-mutant NSCLC cells, xenograft tumors, and patient-derived xenograft (PDX) models. Therefore, combination of EGFR-TKI and AXL degrader is a potentially effective treatment strategy for overcoming and delaying acquired resistance in NSCLC. Nature Publishing Group UK 2019-05-01 /pmc/articles/PMC6494839/ /pubmed/31043587 http://dx.doi.org/10.1038/s41419-019-1601-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kim, Donghwa
Bach, Duc-Hiep
Fan, Yan-Hua
Luu, Thi-Thu-Trang
Hong, Ji-Young
Park, Hyen Joo
Lee, Sang Kook
AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells
title AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells
title_full AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells
title_fullStr AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells
title_full_unstemmed AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells
title_short AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells
title_sort axl degradation in combination with egfr-tki can delay and overcome acquired resistance in human non-small cell lung cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494839/
https://www.ncbi.nlm.nih.gov/pubmed/31043587
http://dx.doi.org/10.1038/s41419-019-1601-6
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