AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1

AZD3759 is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) on the basis of gefitinib and has been proven to enter the central nervous system. Although the promising antitumor effects of AZD3759 on non-small cell lung cancer (NSCLC) have been demonstrated in clinical t...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ruing Zhao, Wei Yin, Qingqing Yu, Yanjiao Mao, Qinghua Deng, Ke Zhang, Shenglin Ma
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	azd3759 osimertinib nsclc egfr mutant jak1 Biotechnology TP248.13-248.65
Acceso en línea:	https://doaj.org/article/6349d74c4c214d8f8b068e0be0c62853
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:6349d74c4c214d8f8b068e0be0c62853
record_format	dspace
spelling	oai:doaj.org-article:6349d74c4c214d8f8b068e0be0c628532021-11-11T14:23:43ZAZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-12165-59792165-598710.1080/21655979.2021.2001238https://doaj.org/article/6349d74c4c214d8f8b068e0be0c628532021-11-01T00:00:00Zhttp://dx.doi.org/10.1080/21655979.2021.2001238https://doaj.org/toc/2165-5979https://doaj.org/toc/2165-5987AZD3759 is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) on the basis of gefitinib and has been proven to enter the central nervous system. Although the promising antitumor effects of AZD3759 on non-small cell lung cancer (NSCLC) have been demonstrated in clinical trials, the regulatory effects of this inhibitor on the antitumor efficacy of radiation (RA) are unclear. The present study aimed to compare the effects of AZD3759 and osimertinib on RA efficacy in NSCLC and explore the potential mechanism of action of AZD3759. We found that the survival in RA-treated NSCLC cells was significantly decreased by treatment with 500 nM AZD3759 and osimertinib at the RA dosage of 8 Gy. The apoptotic rate, cell cycle arrest, and DNA damage in RA-treated NSCLC cells and brain metastasis in RA-treated xenograft nude mice were significantly enhanced by the co-administration of AZD3759 and osimertinib, respectively. In addition, AZD3759 showed a significantly stronger efficacy than osimertinib did. Mechanistically, the receptor tyrosine kinase signaling antibody array revealed that Janus kinase-1 (JAK1) was specifically inhibited by AZD3759, but not by osimertinib. The effects of AZD3759 on RA efficacy in PC-9 cells and in a brain metastasis animal model were significantly abolished by the overexpression of JAK1. Collectively, our results suggested that AZD3759 promoted RA antitumor effects in NSCLC by synergistic blockade of EGFR and JAK1.Ruing ZhaoWei YinQingqing YuYanjiao MaoQinghua DengKe ZhangShenglin MaTaylor & Francis Grouparticleazd3759osimertinibnsclcegfr mutantjak1BiotechnologyTP248.13-248.65ENBioengineered, Vol 0, Iss 0 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	azd3759 osimertinib nsclc egfr mutant jak1 Biotechnology TP248.13-248.65
spellingShingle	azd3759 osimertinib nsclc egfr mutant jak1 Biotechnology TP248.13-248.65 Ruing Zhao Wei Yin Qingqing Yu Yanjiao Mao Qinghua Deng Ke Zhang Shenglin Ma AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1
description	AZD3759 is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) on the basis of gefitinib and has been proven to enter the central nervous system. Although the promising antitumor effects of AZD3759 on non-small cell lung cancer (NSCLC) have been demonstrated in clinical trials, the regulatory effects of this inhibitor on the antitumor efficacy of radiation (RA) are unclear. The present study aimed to compare the effects of AZD3759 and osimertinib on RA efficacy in NSCLC and explore the potential mechanism of action of AZD3759. We found that the survival in RA-treated NSCLC cells was significantly decreased by treatment with 500 nM AZD3759 and osimertinib at the RA dosage of 8 Gy. The apoptotic rate, cell cycle arrest, and DNA damage in RA-treated NSCLC cells and brain metastasis in RA-treated xenograft nude mice were significantly enhanced by the co-administration of AZD3759 and osimertinib, respectively. In addition, AZD3759 showed a significantly stronger efficacy than osimertinib did. Mechanistically, the receptor tyrosine kinase signaling antibody array revealed that Janus kinase-1 (JAK1) was specifically inhibited by AZD3759, but not by osimertinib. The effects of AZD3759 on RA efficacy in PC-9 cells and in a brain metastasis animal model were significantly abolished by the overexpression of JAK1. Collectively, our results suggested that AZD3759 promoted RA antitumor effects in NSCLC by synergistic blockade of EGFR and JAK1.
format	article
author	Ruing Zhao Wei Yin Qingqing Yu Yanjiao Mao Qinghua Deng Ke Zhang Shenglin Ma
author_facet	Ruing Zhao Wei Yin Qingqing Yu Yanjiao Mao Qinghua Deng Ke Zhang Shenglin Ma
author_sort	Ruing Zhao
title	AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1
title_short	AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1
title_full	AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1
title_fullStr	AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1
title_full_unstemmed	AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1
title_sort	azd3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and janus kinase-1
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/6349d74c4c214d8f8b068e0be0c62853
work_keys_str_mv	AT ruingzhao azd3759enhancesradiationeffectsinnonsmallcelllungcancerbyasynergisticblockadeofepidermalgrowthfactorreceptorandjanuskinase1 AT weiyin azd3759enhancesradiationeffectsinnonsmallcelllungcancerbyasynergisticblockadeofepidermalgrowthfactorreceptorandjanuskinase1 AT qingqingyu azd3759enhancesradiationeffectsinnonsmallcelllungcancerbyasynergisticblockadeofepidermalgrowthfactorreceptorandjanuskinase1 AT yanjiaomao azd3759enhancesradiationeffectsinnonsmallcelllungcancerbyasynergisticblockadeofepidermalgrowthfactorreceptorandjanuskinase1 AT qinghuadeng azd3759enhancesradiationeffectsinnonsmallcelllungcancerbyasynergisticblockadeofepidermalgrowthfactorreceptorandjanuskinase1 AT kezhang azd3759enhancesradiationeffectsinnonsmallcelllungcancerbyasynergisticblockadeofepidermalgrowthfactorreceptorandjanuskinase1 AT shenglinma azd3759enhancesradiationeffectsinnonsmallcelllungcancerbyasynergisticblockadeofepidermalgrowthfactorreceptorandjanuskinase1
_version_	1718438940266987520

AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1

Ejemplares similares