TLE1 drives EGFR-TKI resistance in EGFR-mutant lung adenocarcinoma through epithelial to mesenchymal transition.

Targeted therapies using EGFR-TKIs are fundamental treatment options for cases of lung adenocarcinoma harboring sensitizing mutations in EGFR. However, tumor progression to acquired resistance significantly hinders long-term efficacy. While the involvement of transcription factors in EGFR-TKI resistance has been extensively investigated, the contribution of transcriptional co-repressors like Transducin-Like Enhancer of Split 1 (TLE1) remains largely unexplored. This study identifies TLE1 as a mediator of insensitivity to EGFR-TKI treatment in lung adenocarcinoma positive for EGFR mutation. Analysis of patient data indicated that elevated TLE1 level was associated with unfavorable survival outcomes among patients with EGFR-mutant LUAD, underscoring its clinical significance. In vitro, specifically in PC9 and HCC827 cells, exogenous TLE1 expression promoted epithelial-mesenchymal transition (EMT) and reduced cellular response to the EGFR-TKIs gefitinib and osimertinib. Conversely, sole downregulation of endogenous TLE1 expression partially restored drug sensitivity in PC9GR and HCC827GR acquired resistance cell line models. At a mechanistic level, TLE1 functions as a co-repressor, interacting with ZEB1 to suppress E-cadherin expression, a key EMT marker, thereby facilitating resistance. This paper provides first evidence of TLE1 driven EMT-associated failure of EGFR-TKI treatment particularly in EGFR-mutant LUAD through its co-repressor activity. These results underscore the previously underappreciated role of transcriptional co-repressors in therapeutic resistance and position TLE1 as a promising prognostic and therapeutic target. Interventions targeting the TLE1-ZEB1 interaction may represent a new approach to mitigate EGFR-TKI resistance and improve outcomes for patients with EGFR-mutant LUAD.