Lipidomics reveals that sustained SREBP-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in EGFR-mutant lung cancer

Abstract Patients with EGFR mutations in non-small cell lung cancer (NSCLC) have been greatly benefited from gefitinib, however, the therapeutic has failed due to the presence of acquired resistance. In this study, we show that gefitinib significantly induces downregulation of Sterol Regulator Eleme...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Chuncao Xu, Lei Zhang, Daifei Wang, Shiqin Jiang, Di Cao, Zhongxiang Zhao, Min Huang, Jing Jin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/789b9afc2a3142cea1af59cbc141d0a2
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:789b9afc2a3142cea1af59cbc141d0a2
record_format	dspace
spelling	oai:doaj.org-article:789b9afc2a3142cea1af59cbc141d0a22021-11-14T12:12:27ZLipidomics reveals that sustained SREBP-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in EGFR-mutant lung cancer10.1038/s41420-021-00744-12058-7716https://doaj.org/article/789b9afc2a3142cea1af59cbc141d0a22021-11-01T00:00:00Zhttps://doi.org/10.1038/s41420-021-00744-1https://doaj.org/toc/2058-7716Abstract Patients with EGFR mutations in non-small cell lung cancer (NSCLC) have been greatly benefited from gefitinib, however, the therapeutic has failed due to the presence of acquired resistance. In this study, we show that gefitinib significantly induces downregulation of Sterol Regulator Element Binding (SREBP1) in therapy-sensitive cells. However, this was not observed in EGFR mutant NSCLC cells with acquired resistance. Lipidomics analysis showed that gefitinib could differently change the proportion of saturated phospholipids and unsaturated phospholipids in gefitinib-sensitive and acquired-resistant cells. Besides, levels of ROS and MDA were increased upon SREBP1 inhibition and even more upon gefitinib treatment. Importantly, inhibition of SREBP1 sensitizes EGFR-mutant therapy-resistant NSCLC to gefitinib both in vitro and in vivo models. These data suggest that sustained de novo lipogenesis through the maintenance of active SRBEP-1 is a key feature of acquired resistance to gefitinib in EGFR mutant lung cancer. Taken together, targeting SREBP1-induced lipogenesis is a promising approach to overcome acquired resistance to gefitinib in EGFR-mutant lung cancer.Chuncao XuLei ZhangDaifei WangShiqin JiangDi CaoZhongxiang ZhaoMin HuangJing JinNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCell Death Discovery, Vol 7, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671 Chuncao Xu Lei Zhang Daifei Wang Shiqin Jiang Di Cao Zhongxiang Zhao Min Huang Jing Jin Lipidomics reveals that sustained SREBP-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in EGFR-mutant lung cancer
description	Abstract Patients with EGFR mutations in non-small cell lung cancer (NSCLC) have been greatly benefited from gefitinib, however, the therapeutic has failed due to the presence of acquired resistance. In this study, we show that gefitinib significantly induces downregulation of Sterol Regulator Element Binding (SREBP1) in therapy-sensitive cells. However, this was not observed in EGFR mutant NSCLC cells with acquired resistance. Lipidomics analysis showed that gefitinib could differently change the proportion of saturated phospholipids and unsaturated phospholipids in gefitinib-sensitive and acquired-resistant cells. Besides, levels of ROS and MDA were increased upon SREBP1 inhibition and even more upon gefitinib treatment. Importantly, inhibition of SREBP1 sensitizes EGFR-mutant therapy-resistant NSCLC to gefitinib both in vitro and in vivo models. These data suggest that sustained de novo lipogenesis through the maintenance of active SRBEP-1 is a key feature of acquired resistance to gefitinib in EGFR mutant lung cancer. Taken together, targeting SREBP1-induced lipogenesis is a promising approach to overcome acquired resistance to gefitinib in EGFR-mutant lung cancer.
format	article
author	Chuncao Xu Lei Zhang Daifei Wang Shiqin Jiang Di Cao Zhongxiang Zhao Min Huang Jing Jin
author_facet	Chuncao Xu Lei Zhang Daifei Wang Shiqin Jiang Di Cao Zhongxiang Zhao Min Huang Jing Jin
author_sort	Chuncao Xu
title	Lipidomics reveals that sustained SREBP-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in EGFR-mutant lung cancer
title_short	Lipidomics reveals that sustained SREBP-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in EGFR-mutant lung cancer
title_full	Lipidomics reveals that sustained SREBP-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in EGFR-mutant lung cancer
title_fullStr	Lipidomics reveals that sustained SREBP-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in EGFR-mutant lung cancer
title_full_unstemmed	Lipidomics reveals that sustained SREBP-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in EGFR-mutant lung cancer
title_sort	lipidomics reveals that sustained srebp-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in egfr-mutant lung cancer
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/789b9afc2a3142cea1af59cbc141d0a2
work_keys_str_mv	AT chuncaoxu lipidomicsrevealsthatsustainedsrebp1dependentlipogenesisisakeymediatorofgefitinibacquiredresistanceinegfrmutantlungcancer AT leizhang lipidomicsrevealsthatsustainedsrebp1dependentlipogenesisisakeymediatorofgefitinibacquiredresistanceinegfrmutantlungcancer AT daifeiwang lipidomicsrevealsthatsustainedsrebp1dependentlipogenesisisakeymediatorofgefitinibacquiredresistanceinegfrmutantlungcancer AT shiqinjiang lipidomicsrevealsthatsustainedsrebp1dependentlipogenesisisakeymediatorofgefitinibacquiredresistanceinegfrmutantlungcancer AT dicao lipidomicsrevealsthatsustainedsrebp1dependentlipogenesisisakeymediatorofgefitinibacquiredresistanceinegfrmutantlungcancer AT zhongxiangzhao lipidomicsrevealsthatsustainedsrebp1dependentlipogenesisisakeymediatorofgefitinibacquiredresistanceinegfrmutantlungcancer AT minhuang lipidomicsrevealsthatsustainedsrebp1dependentlipogenesisisakeymediatorofgefitinibacquiredresistanceinegfrmutantlungcancer AT jingjin lipidomicsrevealsthatsustainedsrebp1dependentlipogenesisisakeymediatorofgefitinibacquiredresistanceinegfrmutantlungcancer
_version_	1718429354811195392

Lipidomics reveals that sustained SREBP-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in EGFR-mutant lung cancer

Ejemplares similares