251. Transcription factor ZNF263 enhances EGFR-targeted therapeutic response and reduces residual disease in lung adenocarcinoma
- Author
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Liang, Jiaqi, Bi, Guoshu, Sui, Qihai, Zhao, Guangyin, Zhang, Huan, Bian, Yunyi, Chen, Zhencong, Huang, Yiwei, Xi, Junjie, Shi, Yu, Wang, Qun, and Zhan, Cheng
- Abstract
EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) have achieved clinical success in lung adenocarcinoma (LUAD). However, tumors often show profound but transient initial response and then gain resistance. We identify transcription factor ZNF263as being significantly decreased in osimertinib-resistant or drug-tolerant persister LUAD cells and clinical residual tumors. ZNF263overexpression improves the initial response of cells and delays the formation of persister cells with osimertinib treatment. We further show that ZNF263 binds and recruits DNMT1 to the EGFRgene promoter, suppressing EGFRtranscription with DNA hypermethylation. ZNF263 interacts with nuclear EGFR, impairing the EGFR-STAT5 interaction to enhance AURKAexpression. Overexpressing ZNF263also makes tumor cells with wild-type EGFRexpression or refractory EGFR mutations more susceptible to EGFR inhibition. More importantly, lentivirus or adeno-associated virus (AAV)-mediated ZNF263 overexpression synergistically suppresses tumor growth and regrowth with osimertinib treatment in xenograft animal models. These findings suggest that enhancing ZNF263may achieve complete response in LUAD with EGFR-targeted therapies.
- Published
- 2024
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