TGFβ2-mediated epithelial–mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance  

作　　者：Xiao-ming Jiang Yu-lian Xu Luo-wei Yuan Le-le Zhang Mu-yang Huang Zi-han Ye Min-xia Su Xiu-ping Chen Hong Zhu Richard DYe Jin-jian Lu 

机构地区：[1]State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macao,Macao,China [2]Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China

出　　处：《Acta Pharmacologica Sinica》2021年第3期451-459,共9页中国药理学报（英文版）

基　　金：funded by University of Macao(File no.MYRG2018-00165-ICMS and MYRG2016-152-ICMS);National Natural Science Foundation of China(81973516);The Science and Technology Development Fund,Macao SAR(File no.176/2017/A3)。

摘　　要：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.

关 键 词：EGFR mutant non-small cell lung cancer osimertinib resistance TGFP2 epithelial-mesenchymal transition NF-κB 

分 类 号：R96[医药卫生—药理学]