Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer

Abstract Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR...

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Autores principales:	Akiko Takahashi, Masahiro Seike, Mika Chiba, Satoshi Takahashi, Shinji Nakamichi, Masaru Matsumoto, Susumu Takeuchi, Yuji Minegishi, Rintaro Noro, Shinobu Kunugi, Kaoru Kubota, Akihiko Gemma
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Osimertinib Afatinib Ankyrin Repeat Domain (ANKRD1) Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) EGFR-mutant NSCLC Patients Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2d4c5449621342aa816f7c0089346a66
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spelling	oai:doaj.org-article:2d4c5449621342aa816f7c0089346a662021-12-02T11:40:46ZAnkyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer10.1038/s41598-018-33190-82045-2322https://doaj.org/article/2d4c5449621342aa816f7c0089346a662018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33190-8https://doaj.org/toc/2045-2322Abstract Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR-TKIs in EGFR-positive NSCLC patients. We established afatinib- and osimertinib-resistant lung adenocarcinoma cell lines. Exome sequencing, cDNA array and miRNA microarray were performed using the established cell lines to discover novel therapeutic targets associated with the resistance to second-and third-generation EGFR-TKIs. We found that ANKRD1 which is associated with the epithelial-mesenchymal transition (EMT) phenomenon and anti-apoptosis, was overexpressed in the second-and third-generation EGFR-TKIs-resistant cells at the mRNA and protein expression levels. When ANKRD1 was silenced in the EGFR-TKIs-resistant cell lines, afatinib and osimertinib could induce apoptosis of the cell lines. Imatinib could inhibit ANKRD1 expression, resulting in restoration of the sensitivity to afatinib and osimertinib of EGFR-TKI-resistant cells. In EGFR-mutant NSCLC patients, ANKRD1 was overexpressed in the tumor after the failure of EGFR-TKI therapy, especially after long-duration EGFR-TKI treatments. ANKRD1 overexpression which was associated with EMT features and anti-apoptosis, was commonly involved in resistance to second-and third-generation EGFR-TKIs. ANKRD1 inhibition could be a promising therapeutic strategy in EGFR-mutant NSCLC patients.Akiko TakahashiMasahiro SeikeMika ChibaSatoshi TakahashiShinji NakamichiMasaru MatsumotoSusumu TakeuchiYuji MinegishiRintaro NoroShinobu KunugiKaoru KubotaAkihiko GemmaNature PortfolioarticleOsimertinibAfatinibAnkyrin Repeat Domain (ANKRD1)Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs)EGFR-mutant NSCLC PatientsMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-9 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Osimertinib Afatinib Ankyrin Repeat Domain (ANKRD1) Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) EGFR-mutant NSCLC Patients Medicine R Science Q
spellingShingle	Osimertinib Afatinib Ankyrin Repeat Domain (ANKRD1) Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) EGFR-mutant NSCLC Patients Medicine R Science Q Akiko Takahashi Masahiro Seike Mika Chiba Satoshi Takahashi Shinji Nakamichi Masaru Matsumoto Susumu Takeuchi Yuji Minegishi Rintaro Noro Shinobu Kunugi Kaoru Kubota Akihiko Gemma Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer
description	Abstract Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR-TKIs in EGFR-positive NSCLC patients. We established afatinib- and osimertinib-resistant lung adenocarcinoma cell lines. Exome sequencing, cDNA array and miRNA microarray were performed using the established cell lines to discover novel therapeutic targets associated with the resistance to second-and third-generation EGFR-TKIs. We found that ANKRD1 which is associated with the epithelial-mesenchymal transition (EMT) phenomenon and anti-apoptosis, was overexpressed in the second-and third-generation EGFR-TKIs-resistant cells at the mRNA and protein expression levels. When ANKRD1 was silenced in the EGFR-TKIs-resistant cell lines, afatinib and osimertinib could induce apoptosis of the cell lines. Imatinib could inhibit ANKRD1 expression, resulting in restoration of the sensitivity to afatinib and osimertinib of EGFR-TKI-resistant cells. In EGFR-mutant NSCLC patients, ANKRD1 was overexpressed in the tumor after the failure of EGFR-TKI therapy, especially after long-duration EGFR-TKI treatments. ANKRD1 overexpression which was associated with EMT features and anti-apoptosis, was commonly involved in resistance to second-and third-generation EGFR-TKIs. ANKRD1 inhibition could be a promising therapeutic strategy in EGFR-mutant NSCLC patients.
format	article
author	Akiko Takahashi Masahiro Seike Mika Chiba Satoshi Takahashi Shinji Nakamichi Masaru Matsumoto Susumu Takeuchi Yuji Minegishi Rintaro Noro Shinobu Kunugi Kaoru Kubota Akihiko Gemma
author_facet	Akiko Takahashi Masahiro Seike Mika Chiba Satoshi Takahashi Shinji Nakamichi Masaru Matsumoto Susumu Takeuchi Yuji Minegishi Rintaro Noro Shinobu Kunugi Kaoru Kubota Akihiko Gemma
author_sort	Akiko Takahashi
title	Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer
title_short	Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer
title_full	Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer
title_fullStr	Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer
title_full_unstemmed	Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer
title_sort	ankyrin repeat domain 1 overexpression is associated with common resistance to afatinib and osimertinib in egfr-mutant lung cancer
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/2d4c5449621342aa816f7c0089346a66
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Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer

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