Loss of MEN1 function impairs DNA repair capability of pancreatic neuroendocrine tumors.
Endocr Relat Cancer
; 29(4): 225-239, 2022 03 21.
Article
em En
| MEDLINE
| ID: mdl-35171113
ABSTRACT
Somatic MEN1 mutations occur in up to 50% of pancreatic neuroendocrine tumors (PanNETs). Clinical studies have shown that radiation therapy (IR) is effective in a subset of PanNETs, but it remains unclear why some patients respond better to IR than others. Herein, we study whether MEN1 loss of function increases radiosensitivity of PanNETs and determine its effect on DNA double-strand break (DSB) repair. After creating a MEN1 knockout PanNET cell line, we confirmed reduced DSB repair capacity in MEN1-deficient cells and linked these findings to a defect in homologous recombination, as well as reduced BRCA2 expression levels. Consistent with this model, we found that MEN1 mutant cells displayed increased sensitivity to the highly trapping poly (ADP-ribose) polymerase (PARP) 1 inhibitor talazoparib in vitro. Our results suggest that combining IR with PARP inhibition may be beneficial in patients with PanNETs and MEN1 loss of function.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Proteínas Proto-Oncogênicas
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Tumores Neuroendócrinos
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article