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Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma

BACKGROUND: Despite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR‐TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance. METHODS: We used P...

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Autores principales: Park, Hee Sun, Lee, Da‐Hye, Kang, Da Hyun, Yeo, Min‐Kyung, Bae, Goeun, Lee, Dahye, Yoo, Geon, Kim, Ju‐Ock, Moon, Eunyoung, Huh, Yang Hoon, Lee, Sang‐Hee, Jo, Eun‐Kyeong, Cho, Sang Yeon, Lee, Jeong Eun, Chung, Chaeuk
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926029/
https://www.ncbi.nlm.nih.gov/pubmed/33486901
http://dx.doi.org/10.1002/cam4.3734
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author Park, Hee Sun
Lee, Da‐Hye
Kang, Da Hyun
Yeo, Min‐Kyung
Bae, Goeun
Lee, Dahye
Yoo, Geon
Kim, Ju‐Ock
Moon, Eunyoung
Huh, Yang Hoon
Lee, Sang‐Hee
Jo, Eun‐Kyeong
Cho, Sang Yeon
Lee, Jeong Eun
Chung, Chaeuk
author_facet Park, Hee Sun
Lee, Da‐Hye
Kang, Da Hyun
Yeo, Min‐Kyung
Bae, Goeun
Lee, Dahye
Yoo, Geon
Kim, Ju‐Ock
Moon, Eunyoung
Huh, Yang Hoon
Lee, Sang‐Hee
Jo, Eun‐Kyeong
Cho, Sang Yeon
Lee, Jeong Eun
Chung, Chaeuk
author_sort Park, Hee Sun
collection PubMed
description BACKGROUND: Despite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR‐TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance. METHODS: We used PC9, PC9/GR, and HCC827/GR cell lines to evaluate the activation of autophagy and EGFR‐TKI resistance. Chloroquine was applied as an autophagic blocker and verteporfin was utilized as a YAP inhibitor. RESULTS: In this study, we tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR‐TKI‐resistant lung adenocarcinoma. We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR‐TKI‐resistant lung adenocarcinoma. Interestingly, we found for the first time that YAP regulates p62 transcription through ERK, and YAP inhibition can suppress the expression of oncogenic p62. We also confirmed that the expressions of p62 and YAP have a positive correlation in EGFR‐mutant lung adenocarcinoma patients. To block cell survival via perturbing YAP‐p62 axis, we treated EGFR‐TKI‐resistant lung cancer cells with YAP inhibitor verteporfin. Remarkably, verteporfin effectively caused the death of EGFR‐TKI‐resistant lung cancer cells by decreasing the expressions of p62 with oncogenic function, YAP, and its target PD‐L1. So, the cumulative effect of oncogenic p62 should be considered when using autophagy inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1. CONCLUSION: Finally, we suggest that targeting YAP‐p62 signaling axis can be useful to suppress the EGFR‐TKI‐resistant lung cancer. Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD‐L1 at the same time.
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spelling pubmed-79260292021-03-12 Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma Park, Hee Sun Lee, Da‐Hye Kang, Da Hyun Yeo, Min‐Kyung Bae, Goeun Lee, Dahye Yoo, Geon Kim, Ju‐Ock Moon, Eunyoung Huh, Yang Hoon Lee, Sang‐Hee Jo, Eun‐Kyeong Cho, Sang Yeon Lee, Jeong Eun Chung, Chaeuk Cancer Med Cancer Biology BACKGROUND: Despite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR‐TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance. METHODS: We used PC9, PC9/GR, and HCC827/GR cell lines to evaluate the activation of autophagy and EGFR‐TKI resistance. Chloroquine was applied as an autophagic blocker and verteporfin was utilized as a YAP inhibitor. RESULTS: In this study, we tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR‐TKI‐resistant lung adenocarcinoma. We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR‐TKI‐resistant lung adenocarcinoma. Interestingly, we found for the first time that YAP regulates p62 transcription through ERK, and YAP inhibition can suppress the expression of oncogenic p62. We also confirmed that the expressions of p62 and YAP have a positive correlation in EGFR‐mutant lung adenocarcinoma patients. To block cell survival via perturbing YAP‐p62 axis, we treated EGFR‐TKI‐resistant lung cancer cells with YAP inhibitor verteporfin. Remarkably, verteporfin effectively caused the death of EGFR‐TKI‐resistant lung cancer cells by decreasing the expressions of p62 with oncogenic function, YAP, and its target PD‐L1. So, the cumulative effect of oncogenic p62 should be considered when using autophagy inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1. CONCLUSION: Finally, we suggest that targeting YAP‐p62 signaling axis can be useful to suppress the EGFR‐TKI‐resistant lung cancer. Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD‐L1 at the same time. John Wiley and Sons Inc. 2021-01-23 /pmc/articles/PMC7926029/ /pubmed/33486901 http://dx.doi.org/10.1002/cam4.3734 Text en © 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Cancer Biology
Park, Hee Sun
Lee, Da‐Hye
Kang, Da Hyun
Yeo, Min‐Kyung
Bae, Goeun
Lee, Dahye
Yoo, Geon
Kim, Ju‐Ock
Moon, Eunyoung
Huh, Yang Hoon
Lee, Sang‐Hee
Jo, Eun‐Kyeong
Cho, Sang Yeon
Lee, Jeong Eun
Chung, Chaeuk
Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma
title Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma
title_full Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma
title_fullStr Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma
title_full_unstemmed Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma
title_short Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma
title_sort targeting yap‐p62 signaling axis suppresses the egfr‐tki‐resistant lung adenocarcinoma
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926029/
https://www.ncbi.nlm.nih.gov/pubmed/33486901
http://dx.doi.org/10.1002/cam4.3734
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