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Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells

Recently, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized non-small cell lung cancer (NSCLC) treatment. However, resistance remains a major obstacle. Anexelekto (AXL) is a member of receptor tyrosine kinases (RTKs) and shares the same downstream signaling...

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Autores principales: Tian, Yaqiong, Zhang, Zengli, Miao, Liyun, Yang, Zhimin, Yang, Jie, Wang, Yinhua, Qian, Danwen, Cai, Hourong, Wang, Yongsheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cognizant Communication Corporation 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838623/
https://www.ncbi.nlm.nih.gov/pubmed/27712586
http://dx.doi.org/10.3727/096504016X14648701447814
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author Tian, Yaqiong
Zhang, Zengli
Miao, Liyun
Yang, Zhimin
Yang, Jie
Wang, Yinhua
Qian, Danwen
Cai, Hourong
Wang, Yongsheng
author_facet Tian, Yaqiong
Zhang, Zengli
Miao, Liyun
Yang, Zhimin
Yang, Jie
Wang, Yinhua
Qian, Danwen
Cai, Hourong
Wang, Yongsheng
author_sort Tian, Yaqiong
collection PubMed
description Recently, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized non-small cell lung cancer (NSCLC) treatment. However, resistance remains a major obstacle. Anexelekto (AXL) is a member of receptor tyrosine kinases (RTKs) and shares the same downstream signaling pathways with EGFR, such as PI3K/AKT and MAPK/ERK. AXL overexpression in resistant tumors has been implicated in many previous studies in vitro and in vivo. In this study, we further examined whether expression of AXL and its downstream targets increased in gefitinib-resistant PC9 cells (PC9GR). In addition, we hypothesize that knocking down AXL in PC9GR and overexpressing AXL in PC9 using genetic tools can restore and decrease the sensitivity to gefitinib, respectively. We found that silencing AXL could sensitize the resistance to gefitinib, and the downstream pathways were significantly inhibited. Interestingly, we also discovered that increased AXL expression did promote the resistance, and its downstream targets were activated accordingly. Then 69 NSCLC patients who harbored EGFR mutation were recruited to analyze the expression of AXL and the association between AXL expression and clinical characteristics. We found that 5 of the 69 patients were AXL positive (about 7%), and AXL was related to tumor differentiation and tumor size. In this study, we concluded that the molecular mechanisms of AXL mediated resistance involved in the increased activity of the PI3K/AKT and MAPK/ERK1/2 pathways, and AXL overexpression could promote resistance, but it can be weakened when AXL expression is silenced.
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spelling pubmed-78386232021-02-16 Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells Tian, Yaqiong Zhang, Zengli Miao, Liyun Yang, Zhimin Yang, Jie Wang, Yinhua Qian, Danwen Cai, Hourong Wang, Yongsheng Oncol Res Article Recently, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized non-small cell lung cancer (NSCLC) treatment. However, resistance remains a major obstacle. Anexelekto (AXL) is a member of receptor tyrosine kinases (RTKs) and shares the same downstream signaling pathways with EGFR, such as PI3K/AKT and MAPK/ERK. AXL overexpression in resistant tumors has been implicated in many previous studies in vitro and in vivo. In this study, we further examined whether expression of AXL and its downstream targets increased in gefitinib-resistant PC9 cells (PC9GR). In addition, we hypothesize that knocking down AXL in PC9GR and overexpressing AXL in PC9 using genetic tools can restore and decrease the sensitivity to gefitinib, respectively. We found that silencing AXL could sensitize the resistance to gefitinib, and the downstream pathways were significantly inhibited. Interestingly, we also discovered that increased AXL expression did promote the resistance, and its downstream targets were activated accordingly. Then 69 NSCLC patients who harbored EGFR mutation were recruited to analyze the expression of AXL and the association between AXL expression and clinical characteristics. We found that 5 of the 69 patients were AXL positive (about 7%), and AXL was related to tumor differentiation and tumor size. In this study, we concluded that the molecular mechanisms of AXL mediated resistance involved in the increased activity of the PI3K/AKT and MAPK/ERK1/2 pathways, and AXL overexpression could promote resistance, but it can be weakened when AXL expression is silenced. Cognizant Communication Corporation 2016-09-14 /pmc/articles/PMC7838623/ /pubmed/27712586 http://dx.doi.org/10.3727/096504016X14648701447814 Text en Copyright © 2016 Cognizant, LLC. http://creativecommons.org/licenses/by-nc-nd/4.0/ This article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License.
spellingShingle Article
Tian, Yaqiong
Zhang, Zengli
Miao, Liyun
Yang, Zhimin
Yang, Jie
Wang, Yinhua
Qian, Danwen
Cai, Hourong
Wang, Yongsheng
Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells
title Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells
title_full Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells
title_fullStr Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells
title_full_unstemmed Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells
title_short Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells
title_sort anexelekto (axl) increases resistance to egfr-tki and activation of akt and erk1/2 in non-small cell lung cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838623/
https://www.ncbi.nlm.nih.gov/pubmed/27712586
http://dx.doi.org/10.3727/096504016X14648701447814
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