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 D.Ye Jin-jian Lu
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（3）
• 所属期刊栏目: Chemotherapy
• 页码范围: 451-459
• 页数: 9页
• 语种: 英文

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 15,3R-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.