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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Transcription factor ZNF263 enhances EGFR-targeted therapeutic response and reduces residual disease in lung
Jiaqi Liang1, Guoshu Bi1, Qihai Sui1
1Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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 ZNF263 as being significantly decreased in osimertinib-resistant or drug-tolerant persister LUAD cells and clinical residual tumors. ZNF263 overexpression 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 EGFR gene promoter, suppressing EGFR transcription with DNA hypermethylation. ZNF263 interacts with nuclear EGFR, impairing the EGFR-STAT5 interaction to enhance AURKA expression. Overexpressing ZNF263 also makes tumor cells with wild-type EGFR expression 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 ZNF263 may achieve complete response in LUAD with EGFR-targeted therapies.
Insights
Decreased ZNF263 is linked to resistance in lung adenocarcinoma (LUAD) treated with EGFR inhibitors. Enhancing ZNF263 may overcome resistance and improve treatment outcomes for LUAD patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against lung adenocarcinoma (LUAD).
- Tumor resistance to EGFR TKIs, such as osimertinib, remains a significant clinical challenge.
- Understanding resistance mechanisms is crucial for improving LUAD treatment efficacy.
Purpose of the Study:
- To identify novel factors involved in osimertinib resistance in LUAD.
- To investigate the role of ZNF263 in regulating EGFR signaling and mediating TKI response.
- To explore ZNF263 as a potential therapeutic target for overcoming EGFR TKI resistance.
Main Methods:
- Analysis of ZNF263 expression in osimertinib-resistant LUAD cells and patient tumors.
- Overexpression of ZNF263 in LUAD cell lines and assessment of osimertinib sensitivity.
- Chromatin immunoprecipitation and methylation analysis to study ZNF263's effect on EGFR promoter.
- Investigation of ZNF263 interactions with EGFR and downstream signaling pathways.
- In vivo studies using xenograft models with lentivirus or AAV-mediated ZNF263 delivery.
Main Results:
- ZNF263 expression is significantly decreased in drug-tolerant persister LUAD cells and residual tumors.
- ZNF263 overexpression enhances initial response to osimertinib and delays resistance.
- ZNF263 suppresses EGFR transcription via DNA hypermethylation by recruiting DNMT1.
- ZNF263 impairs EGFR-STAT5 interaction, affecting AURKA expression.
- ZNF263 overexpression sensitizes wild-type EGFR and resistant EGFR-mutant LUAD cells to EGFR inhibition.
- ZNF263 delivery via viral vectors synergistically inhibits tumor growth and regrowth with osimertinib in vivo.
Conclusions:
- ZNF263 is a critical suppressor of EGFR transcription and a mediator of sensitivity to EGFR TKIs in LUAD.
- Restoring ZNF263 levels can overcome osimertinib resistance by epigenetically silencing EGFR.
- ZNF263 represents a promising therapeutic target for enhancing the efficacy of EGFR-targeted therapies in LUAD.
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