Loss of MEN1 function impairs DNA repair capability of pancreatic neuroendocrine tumors
| Autor: | Olga Lakiza, Julian Lutze, Alyx Vogle, Jelani Williams, Abde Abukdheir, Paul Miller, Chih-Yi ‘Andy’ Liao, Sean P Pitroda, Carlos Martinez, Andrea Olivas, Namrata Setia, Stephen J Kron, Ralph R Weichselbaum, Xavier M Keutgen |
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| Rok vydání: | 2022 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities endocrine system Cancer Research DNA Repair endocrine system diseases Endocrinology Diabetes and Metabolism Poly(ADP-ribose) Polymerase Inhibitors Article Pancreatic Neoplasms Neuroendocrine Tumors Endocrinology Oncology Proto-Oncogene Proteins Humans Poly(ADP-ribose) Polymerases |
| Zdroj: | Endocr Relat Cancer |
| ISSN: | 1479-6821 1351-0088 |
| DOI: | 10.1530/erc-21-0247 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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