Transcription factor ZNF263 enhances EGFR-targeted therapeutic response and reduces residual disease in lung adenocarcinoma.

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. [Display omitted] • Loss of ZNF263 expression occurs in EGFR TKI-residual lung adenocarcinoma • ZNF263 overexpression combats tumor cell survival and resistance to EGFR inhibition • ZNF263 suppresses the EGFR expression and disrupts the nuclear function of EGFR • AAV-ZNF263 is promising for achieving durable response to EGFR-targeted therapies Liang et al. show that ZNF263 expression is decreased in response to EGFR inhibition in lung adenocarcinoma. ZNF263 expression decrease contributes to cell persistence and resistance by enhancing EGFR expression and its nuclear activity. The authors show that overexpressing ZNF263 in tumors may achieve complete response with EGFR-targeted therapies. [ABSTRACT FROM AUTHOR]