Predictive biomarkers for response to TGF- ß inhibition in resensitizing chemo(radiated) esophageal adenocarcinoma.
Pharmacol Res
; 207: 107315, 2024 Sep.
Article
en En
| MEDLINE
| ID: mdl-39059615
ABSTRACT
Epithelial-mesenchymal transition (EMT) has been identified as a driver of therapy resistance, particularly in esophageal adenocarcinoma (EAC), where transforming growth factor beta (TGF-ß) can induce this process. Inhibitors of TGF-ß may counteract the occurrence of mesenchymal, resistant tumor cell populations following chemo(radio)therapy and improve treatment outcomes in EAC. Here, we aimed to identify predictive biomarkers for the response to TGF-ß targeting. In vitro approximations of neoadjuvant treatment were applied to publicly available primary EAC cell lines. TGF-ß inhibitors fresolimumab and A83-01 were employed to inhibit EMT, and mesenchymal markers were quantified via flow cytometry to assess efficacy. Our results demonstrated a robust induction of mesenchymal cell states following chemoradiation, with TGF-ß inhibition leading to variable reductions in mesenchymal markers. The cell lines were clustered into responders and non-responders. Genomic expression profiles were obtained through RNA-seq analysis. Differentially expressed gene (DEG) analysis identified 10 positively- and 23 negatively-associated hub genes, which were bioinformatically identified. Furthermore, the correlation of DEGs with response to TGF-ß inhibition was examined using public pharmacogenomic databases, revealing 9 positively associated and 11 negatively associated DEGs. Among these, ERBB2, EFNB1, and TNS4 were the most promising candidates. Our findings reveal a distinct gene expression pattern associated with the response to TGF-ß inhibition in chemo(radiated) EAC. The identified DEGs and predictive markers may assist patient selection in clinical studies investigating TGF-ß targeting.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Esofágicas
/
Adenocarcinoma
/
Biomarcadores de Tumor
/
Factor de Crecimiento Transformador beta
/
Transición Epitelial-Mesenquimal
Límite:
Humans
Idioma:
En
Revista:
Pharmacol Res
Asunto de la revista:
FARMACOLOGIA
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Países Bajos