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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
Source PublicationActa Pharmacologica Sinica
ISSN1671-4083
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]:3   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
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
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.
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.
MLA Jiang,Xiao ming,et al."TGFβ2-mediated epithelial–mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance".Acta Pharmacologica Sinica (2020).
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