期刊
ACTA PHARMACOLOGICA SINICA
卷 42, 期 3, 页码 451-459出版社
NATURE PUBL GROUP
DOI: 10.1038/s41401-020-0457-8
关键词
EGFR mutant non-small cell lung cancer; osimertinib resistance; TGF beta 2; epithelial-mesenchymal transition; NF-kappa B
资金
- University of Macau [MYRG2018-00165-ICMS, MYRG2016-152-ICMS]
- National Natural Science Foundation of China [81973516]
- Science and Technology Development Fund, Macau SAR [176/2017/A3]
The study elucidated the resistance mechanisms in osimertinib-resistant cells, involving EMT and activation of the NF-kappa B pathway. TGF beta 2 plays a crucial role in osimertinib-resistant cells and is associated with cell death and NF-kappa B pathway activation.
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 TGF beta 2 that activated SMAD2. On the other hand, we revealed that NCI-H1975/OSIR cells were highly dependent on NF-kappa B pathway for survival, since treatment with the NF-kappa B 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-kappa B pathway, evidenced by the increased p65 nuclear translocation, which was abolished by knockdown of TGF beta 2. In the cancer genome atlas lung adenocarcinoma data, TGFB2 transcript abundance significantly correlated with EMT-associated genes and NF-kappa B pathway. In addition, coexistence of EMT and activation of NF-kappa B pathway was observed in several NCI-H1975/OSIR clones. These findings shed new light on distinct roles of TGF beta 2 in osimertinib-resistant cells and provide new strategies for treatment of this resistant status.
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