Combining EGFR-TKI With SAHA Overcomes EGFR-TKI-Acquired Resistance by Reducing the Protective Autophagy in Non-Small Cell Lung Cancer
Nowadays, lung cancer has the highest mortality worldwide. The emergence of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has greatly improved the survival of patients with non-small cell lung cancer (NSCLC) having EGFR-TKI-sensitive mutations. Unfortunately, acquired res...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990828/ https://www.ncbi.nlm.nih.gov/pubmed/35402377 http://dx.doi.org/10.3389/fchem.2022.837987 |
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author | Cao, Peijun Li, Yongwen Shi, Ruifeng Yuan, Yin Gong, Hao Zhu, Guangsheng Zhang, Zihe Chen, Chen Zhang, Hongbing Liu, Minghui Pan, Zhenhua Liu, Hongyu Chen, Jun |
author_facet | Cao, Peijun Li, Yongwen Shi, Ruifeng Yuan, Yin Gong, Hao Zhu, Guangsheng Zhang, Zihe Chen, Chen Zhang, Hongbing Liu, Minghui Pan, Zhenhua Liu, Hongyu Chen, Jun |
author_sort | Cao, Peijun |
collection | PubMed |
description | Nowadays, lung cancer has the highest mortality worldwide. The emergence of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has greatly improved the survival of patients with non-small cell lung cancer (NSCLC) having EGFR-TKI-sensitive mutations. Unfortunately, acquired resistance happens for most patients. In the present research, we found that EGFR-TKIs (such as gefitinib and osimertinib) can induce autophagy in NSCLC cell lines. Compared with parental sensitive cells, drug-resistant cells have higher autophagy activity. The use of an autophagy inhibitor could enhance the toxicity of gefitinib and osimertinib, which indicates that the enhancement of protective autophagy might be one of the mechanisms of EGFR-TKI resistance in NSCLC. In addition, increased autophagy activity is associated with decreased enhancer of zeste homolog 2 (EZH2) expression. Knockdown of EZH2 or EZH2 inhibitor treatment could lead to increased autophagy in NSCLC cells, indicating that EZH2 is a negative regulator of autophagy. We revealed that the increase in autophagy caused by the reduction of EZH2 was reversed in vitro and in vivo when combining gefitinib or osimertinib with suberoylanilide hydroxamic acid (SAHA), a broad-spectrum histone deacetylase inhibitor (HDACi). In conclusion, our results indicated that the combination of EGFR-TKIs and SAHA may be a new strategy to overcome EGFR-TKIs acquired resistance. |
format | Online Article Text |
id | pubmed-8990828 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89908282022-04-09 Combining EGFR-TKI With SAHA Overcomes EGFR-TKI-Acquired Resistance by Reducing the Protective Autophagy in Non-Small Cell Lung Cancer Cao, Peijun Li, Yongwen Shi, Ruifeng Yuan, Yin Gong, Hao Zhu, Guangsheng Zhang, Zihe Chen, Chen Zhang, Hongbing Liu, Minghui Pan, Zhenhua Liu, Hongyu Chen, Jun Front Chem Chemistry Nowadays, lung cancer has the highest mortality worldwide. The emergence of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has greatly improved the survival of patients with non-small cell lung cancer (NSCLC) having EGFR-TKI-sensitive mutations. Unfortunately, acquired resistance happens for most patients. In the present research, we found that EGFR-TKIs (such as gefitinib and osimertinib) can induce autophagy in NSCLC cell lines. Compared with parental sensitive cells, drug-resistant cells have higher autophagy activity. The use of an autophagy inhibitor could enhance the toxicity of gefitinib and osimertinib, which indicates that the enhancement of protective autophagy might be one of the mechanisms of EGFR-TKI resistance in NSCLC. In addition, increased autophagy activity is associated with decreased enhancer of zeste homolog 2 (EZH2) expression. Knockdown of EZH2 or EZH2 inhibitor treatment could lead to increased autophagy in NSCLC cells, indicating that EZH2 is a negative regulator of autophagy. We revealed that the increase in autophagy caused by the reduction of EZH2 was reversed in vitro and in vivo when combining gefitinib or osimertinib with suberoylanilide hydroxamic acid (SAHA), a broad-spectrum histone deacetylase inhibitor (HDACi). In conclusion, our results indicated that the combination of EGFR-TKIs and SAHA may be a new strategy to overcome EGFR-TKIs acquired resistance. Frontiers Media S.A. 2022-03-25 /pmc/articles/PMC8990828/ /pubmed/35402377 http://dx.doi.org/10.3389/fchem.2022.837987 Text en Copyright © 2022 Cao, Li, Shi, Yuan, Gong, Zhu, Zhang, Chen, Zhang, Liu, Pan, Liu and Chen. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Chemistry Cao, Peijun Li, Yongwen Shi, Ruifeng Yuan, Yin Gong, Hao Zhu, Guangsheng Zhang, Zihe Chen, Chen Zhang, Hongbing Liu, Minghui Pan, Zhenhua Liu, Hongyu Chen, Jun Combining EGFR-TKI With SAHA Overcomes EGFR-TKI-Acquired Resistance by Reducing the Protective Autophagy in Non-Small Cell Lung Cancer |
title | Combining EGFR-TKI With SAHA Overcomes EGFR-TKI-Acquired Resistance by Reducing the Protective Autophagy in Non-Small Cell Lung Cancer |
title_full | Combining EGFR-TKI With SAHA Overcomes EGFR-TKI-Acquired Resistance by Reducing the Protective Autophagy in Non-Small Cell Lung Cancer |
title_fullStr | Combining EGFR-TKI With SAHA Overcomes EGFR-TKI-Acquired Resistance by Reducing the Protective Autophagy in Non-Small Cell Lung Cancer |
title_full_unstemmed | Combining EGFR-TKI With SAHA Overcomes EGFR-TKI-Acquired Resistance by Reducing the Protective Autophagy in Non-Small Cell Lung Cancer |
title_short | Combining EGFR-TKI With SAHA Overcomes EGFR-TKI-Acquired Resistance by Reducing the Protective Autophagy in Non-Small Cell Lung Cancer |
title_sort | combining egfr-tki with saha overcomes egfr-tki-acquired resistance by reducing the protective autophagy in non-small cell lung cancer |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990828/ https://www.ncbi.nlm.nih.gov/pubmed/35402377 http://dx.doi.org/10.3389/fchem.2022.837987 |
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