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TGFβ2-mediated epithelial–mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance
Jiang,Xiao ming1; Xu,Yu lian1; Yuan,Luo wei1; Zhang,Le le1; Huang,Mu yang1; Ye,Zi han1; Su,Min xia1; Chen,Xiu ping1; Zhu,Hong2; Ye,Richard D.1; Lu,Jin jian1
2020-07-16
Source PublicationActa Pharmacologica Sinica
ISSN1671-4083
Volume42Issue:3Pages:451-459
Abstract

Osimertinib (AZD9291) has been widely used for the treatment of EGFR mutant non-small cell lung cancer. However, resistance to osimertinib is inevitable. In this study we elucidated the molecular mechanisms of resistance in osimertinib-resistant NCI-H1975/OSIR cells. We showed that NCI-H1975/OSIR cells underwent epithelial–mesenchymal transition (EMT), which conferred sensitivity to the GPX4 inhibitor 1S, 3R-RSL3 to induce ferroptotic cell death. The EMT occurrence resulted from osimertinib-induced upregulation of TGFβ2 that activated SMAD2. On the other hand, we revealed that NCI-H1975/OSIR cells were highly dependent on NF-κB pathway for survival, since treatment with the NF-κB pathway inhibitor BAY 11–7082 or genetic silence of p65 caused much greater cell death as compared with the parental NCI-H1975 cells. In NCI-H1975 cells, osimertinib activated NF-κB pathway, evidenced by the increased p65 nuclear translocation, which was abolished by knockdown of TGFβ2. In the cancer genome atlas lung adenocarcinoma data, TGFB2 transcript abundance significantly correlated with EMT-associated genes and NF-κB pathway. In addition, coexistence of EMT and activation of NF-κB pathway was observed in several NCI-H1975/OSIR clones. These findings shed new light on distinct roles of TGFβ2 in osimertinib-resistant cells and provide new strategies for treatment of this resistant status.

KeywordEgfr Mutant Non-small Cell Lung Cancer Epithelial-mesenchymal Transition Nf-κb Osimertinib Resistance Tgfβ2
DOI10.1038/s41401-020-0457-8
URLView the original
Indexed BySCIE
WOS Research AreaChemistry ; Pharmacology & Pharmacy
WOS SubjectChemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS IDWOS:000549249000001
Scopus ID2-s2.0-85087944268
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Cited Times [WOS]:4   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorLu,Jin jian
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macau,Macao
2.Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,310058,China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Jiang,Xiao ming,Xu,Yu lian,Yuan,Luo wei,et al. TGFβ2-mediated epithelial–mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance[J]. Acta Pharmacologica Sinica,2020,42(3):451-459.
APA Jiang,Xiao ming,Xu,Yu lian,Yuan,Luo wei,Zhang,Le le,Huang,Mu yang,Ye,Zi han,Su,Min xia,Chen,Xiu ping,Zhu,Hong,Ye,Richard D.,&Lu,Jin jian.(2020).TGFβ2-mediated epithelial–mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance.Acta Pharmacologica Sinica,42(3),451-459.
MLA Jiang,Xiao ming,et al."TGFβ2-mediated epithelial–mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance".Acta Pharmacologica Sinica 42.3(2020):451-459.
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