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.
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Data availability
Datasets used and/or analyzed during the current study are deposited at https://doi.org/10.6084/m9.figshare.11653641.v1 or from the cBioPortal website.
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Acknowledgements
This study was funded by University of Macau (File no. MYRG2018-00165-ICMS and MYRG2016-152-ICMS), National Natural Science Foundation of China (81973516) and The Science and Technology Development Fund, Macau SAR (File no. 176/2017/A3). The results of gene expression profiling shown here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.
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XMJ and JJL designed the research. XMJ, YLX, LWY, MYH, ZHY, and MXS conducted the experiments. XMJ and LLZ contributed to data analysis. XMJ and JJL wrote the paper. JJL, XPC, RDY, and HZ revised the paper. All authors provided final approval of the paper.
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Jiang, Xm., Xu, Yl., Yuan, Lw. et al. TGFβ2-mediated epithelial–mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance. Acta Pharmacol Sin 42, 451–459 (2021). https://doi.org/10.1038/s41401-020-0457-8
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DOI: https://doi.org/10.1038/s41401-020-0457-8
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