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Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR‐mutant non‐small cell lung cancer

BACKGROUND: The resistance mechanism of the third generation of epidermal growth factor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is complex. Epithelial mesenchymal transition (EMT) is a common mechanism of EGFR‐TKI acquired resistance. Snail is an important transcription factor related to...

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Autores principales: Qin, Qiong, Li, Xiaoqing, Liang, Xingmei, Zeng, Lili, Wang, Jing, Sun, Linlin, Zhong, Diansheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons Australia, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169301/
https://www.ncbi.nlm.nih.gov/pubmed/33943009
http://dx.doi.org/10.1111/1759-7714.13906
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author Qin, Qiong
Li, Xiaoqing
Liang, Xingmei
Zeng, Lili
Wang, Jing
Sun, Linlin
Zhong, Diansheng
author_facet Qin, Qiong
Li, Xiaoqing
Liang, Xingmei
Zeng, Lili
Wang, Jing
Sun, Linlin
Zhong, Diansheng
author_sort Qin, Qiong
collection PubMed
description BACKGROUND: The resistance mechanism of the third generation of epidermal growth factor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is complex. Epithelial mesenchymal transition (EMT) is a common mechanism of EGFR‐TKI acquired resistance. Snail is an important transcription factor related to EMT. Whether targeting Snail can reverse the resistance of osimertinib by downregulating Snail is unknown. METHODS: The presence of EMT in H1975/OR (osimertinib resistance) cells was confirmed by transwell assay. To explore the EMT role in resistance, the expression levels of EMT markers were detected in both parental cells H1975 and resistant cells H1975OR. We used RNA interference technology to knockdown the key regulator Snail in resistant cells. After the interference efficiency was confirmed, changes in EMT‐related molecules of Snail were explicitly downregulated, and changes in sensitivity and migration and invasion ability were also examined. We used CDK4/6 inhibitor to test the ability of reversing drug resistance by downregulating Snail. RESULTS: Compared with the H1975 cell line, the H1975/OR resistant cell line showed increased invasiveness, upregulated expression of vimentin and downregulation of E‐cadherin. EMT occurred in the H1975/OR resistant cell line. The expression of Snail was upregulated in the osimertinib‐resistant cell line H1975/OR. Knockdown of Snail increased the sensitivity of H1975/OR cells to osimertinib. CDK4/6 inhibitor palbociclib could downregulate the expression of Snail. CDK 4/6 inhibitor palbociclib combined with osimertinib could reverse the resistance of osimertinib in H1975/OR. CONCLUSIONS: Snail plays an important role in the third generation of EGFR‐TKI osimertinib resistance, which may be reversed by downregulating Snail.
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spelling pubmed-81693012021-06-05 Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR‐mutant non‐small cell lung cancer Qin, Qiong Li, Xiaoqing Liang, Xingmei Zeng, Lili Wang, Jing Sun, Linlin Zhong, Diansheng Thorac Cancer Original Articles BACKGROUND: The resistance mechanism of the third generation of epidermal growth factor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is complex. Epithelial mesenchymal transition (EMT) is a common mechanism of EGFR‐TKI acquired resistance. Snail is an important transcription factor related to EMT. Whether targeting Snail can reverse the resistance of osimertinib by downregulating Snail is unknown. METHODS: The presence of EMT in H1975/OR (osimertinib resistance) cells was confirmed by transwell assay. To explore the EMT role in resistance, the expression levels of EMT markers were detected in both parental cells H1975 and resistant cells H1975OR. We used RNA interference technology to knockdown the key regulator Snail in resistant cells. After the interference efficiency was confirmed, changes in EMT‐related molecules of Snail were explicitly downregulated, and changes in sensitivity and migration and invasion ability were also examined. We used CDK4/6 inhibitor to test the ability of reversing drug resistance by downregulating Snail. RESULTS: Compared with the H1975 cell line, the H1975/OR resistant cell line showed increased invasiveness, upregulated expression of vimentin and downregulation of E‐cadherin. EMT occurred in the H1975/OR resistant cell line. The expression of Snail was upregulated in the osimertinib‐resistant cell line H1975/OR. Knockdown of Snail increased the sensitivity of H1975/OR cells to osimertinib. CDK4/6 inhibitor palbociclib could downregulate the expression of Snail. CDK 4/6 inhibitor palbociclib combined with osimertinib could reverse the resistance of osimertinib in H1975/OR. CONCLUSIONS: Snail plays an important role in the third generation of EGFR‐TKI osimertinib resistance, which may be reversed by downregulating Snail. John Wiley & Sons Australia, Ltd 2021-05-04 2021-06 /pmc/articles/PMC8169301/ /pubmed/33943009 http://dx.doi.org/10.1111/1759-7714.13906 Text en © 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Qin, Qiong
Li, Xiaoqing
Liang, Xingmei
Zeng, Lili
Wang, Jing
Sun, Linlin
Zhong, Diansheng
Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR‐mutant non‐small cell lung cancer
title Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR‐mutant non‐small cell lung cancer
title_full Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR‐mutant non‐small cell lung cancer
title_fullStr Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR‐mutant non‐small cell lung cancer
title_full_unstemmed Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR‐mutant non‐small cell lung cancer
title_short Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR‐mutant non‐small cell lung cancer
title_sort targeting the emt transcription factor snail overcomes resistance to osimertinib in egfr‐mutant non‐small cell lung cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169301/
https://www.ncbi.nlm.nih.gov/pubmed/33943009
http://dx.doi.org/10.1111/1759-7714.13906
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