Contribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer

Abstract The emergence of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with activating EGFR mutations is a major hindrance to treatment. We investigated the effects of p53 in primary sensitivity and acquired resistance...

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Autores principales:	Sangyong Jung, Dong Ha Kim, Yun Jung Choi, Seon Ye Kim, Hyojeong Park, Hyeonjeong Lee, Chang-Min Choi, Young Hoon Sung, Jae Cheol Lee, Jin Kyung Rho
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4f71769b43da4ae2a10dadce8fbefd82
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spelling	oai:doaj.org-article:4f71769b43da4ae2a10dadce8fbefd822021-12-02T18:01:48ZContribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer10.1038/s41598-021-99267-z2045-2322https://doaj.org/article/4f71769b43da4ae2a10dadce8fbefd822021-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-99267-zhttps://doaj.org/toc/2045-2322Abstract The emergence of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with activating EGFR mutations is a major hindrance to treatment. We investigated the effects of p53 in primary sensitivity and acquired resistance to EGFR-TKIs in NSCLC cells. Changes in sensitivity to EGFR-TKIs were determined using p53 overexpression or knockdown in cells with activating EGFR mutations. We investigated EMT-related molecules, morphologic changes, and AXL induction to elucidate mechanisms of acquired resistance to EGFR-TKIs according to p53 status. Changes in p53 status affected primary sensitivity as well as acquired resistance to EGFR-TKIs according to cell type. Firstly, p53 silencing did not affect primary and acquired resistance to EGFR-TKIs in PC-9 cells, but it led to primary resistance to EGFR-TKIs through AXL induction in HCC827 cells. Secondly, p53 silencing in H1975 cells enhanced the sensitivity to osimertinib through the emergence of mesenchymal-to-epithelial transition, and the emergence of acquired resistance to osimertinib in p53 knockout cells was much slower than in H1975 cells. Furthermore, two cell lines (H1975 and H1975/p53KO) demonstrated the different mechanisms of acquired resistance to osimertinib. Lastly, the introduction of mutant p53-R273H induced the epithelial-to-mesenchymal transition and exerted resistance to EGFR-TKIs in cells with activating EGFR mutations. These findings indicate that p53 mutations can be associated with primary or acquired resistance to EGFR-TKIs. Thus, the status or mutations of p53 may be considered as routes to improving the therapeutic effects of EGFR-TKIs in NSCLC.Sangyong JungDong Ha KimYun Jung ChoiSeon Ye KimHyojeong ParkHyeonjeong LeeChang-Min ChoiYoung Hoon SungJae Cheol LeeJin Kyung RhoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sangyong Jung Dong Ha Kim Yun Jung Choi Seon Ye Kim Hyojeong Park Hyeonjeong Lee Chang-Min Choi Young Hoon Sung Jae Cheol Lee Jin Kyung Rho Contribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
description	Abstract The emergence of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with activating EGFR mutations is a major hindrance to treatment. We investigated the effects of p53 in primary sensitivity and acquired resistance to EGFR-TKIs in NSCLC cells. Changes in sensitivity to EGFR-TKIs were determined using p53 overexpression or knockdown in cells with activating EGFR mutations. We investigated EMT-related molecules, morphologic changes, and AXL induction to elucidate mechanisms of acquired resistance to EGFR-TKIs according to p53 status. Changes in p53 status affected primary sensitivity as well as acquired resistance to EGFR-TKIs according to cell type. Firstly, p53 silencing did not affect primary and acquired resistance to EGFR-TKIs in PC-9 cells, but it led to primary resistance to EGFR-TKIs through AXL induction in HCC827 cells. Secondly, p53 silencing in H1975 cells enhanced the sensitivity to osimertinib through the emergence of mesenchymal-to-epithelial transition, and the emergence of acquired resistance to osimertinib in p53 knockout cells was much slower than in H1975 cells. Furthermore, two cell lines (H1975 and H1975/p53KO) demonstrated the different mechanisms of acquired resistance to osimertinib. Lastly, the introduction of mutant p53-R273H induced the epithelial-to-mesenchymal transition and exerted resistance to EGFR-TKIs in cells with activating EGFR mutations. These findings indicate that p53 mutations can be associated with primary or acquired resistance to EGFR-TKIs. Thus, the status or mutations of p53 may be considered as routes to improving the therapeutic effects of EGFR-TKIs in NSCLC.
format	article
author	Sangyong Jung Dong Ha Kim Yun Jung Choi Seon Ye Kim Hyojeong Park Hyeonjeong Lee Chang-Min Choi Young Hoon Sung Jae Cheol Lee Jin Kyung Rho
author_facet	Sangyong Jung Dong Ha Kim Yun Jung Choi Seon Ye Kim Hyojeong Park Hyeonjeong Lee Chang-Min Choi Young Hoon Sung Jae Cheol Lee Jin Kyung Rho
author_sort	Sangyong Jung
title	Contribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
title_short	Contribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
title_full	Contribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
title_fullStr	Contribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
title_full_unstemmed	Contribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
title_sort	contribution of p53 in sensitivity to egfr tyrosine kinase inhibitors in non-small cell lung cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4f71769b43da4ae2a10dadce8fbefd82
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Contribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer

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