@article{APS10288,
author = {Xiao-ming Jiang and Yu-lian Xu and Luo-wei Yuan and Le-le Zhang and Mu-yang Huang and Zi-han Ye and Min-xia Su and Xiu-ping Chen and Hong Zhu and Richard D. Ye and Jin-jian Lu},
title = {TGFβ2-mediated epithelial–mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance},
journal = {Acta Pharmacologica Sinica},
volume = {42},
number = {3},
year = {2021},
keywords = {},
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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/10288}
}