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- Title
Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth.
- Authors
Della Monica, Rosa; Buonaiuto, Michela; Cuomo, Mariella; Pagano, Cristina; Trio, Federica; Costabile, Davide; de Riso, Giulia; Cicala, Francesca Sveva; Raia, Maddalena; Franca, Raduan Ahmed; Del Basso De Caro, Marialaura; Sorrentino, Domenico; Navarra, Giovanna; Coppola, Laura; Tripodi, Lorella; Pastore, Lucio; Hench, Juergen; Frank, Stephan; Schonauer, Claudio; Catapano, Giuseppe
- Abstract
Despite intense research efforts, glioblastoma remains an incurable brain tumor with a dismal median survival time of 15 months. Thus, identifying new therapeutic targets is an urgent need. Here, we show that the lysine methyltransferase SETD8 is overexpressed in 50% of high-grade gliomas. The small molecule SETD8 inhibitor UNC0379, as well as siRNA-mediated inhibition of SETD8, blocked glioblastoma cell proliferation, by inducing DNA damage and activating cell cycle checkpoints. Specifically, in p53-proficient glioblastoma cells, SETD8 inhibition and DNA damage induced p21 accumulation and G1/S arrest whereas, in p53-deficient glioblastoma cells, DNA damage induced by SETD8 inhibition resulted in G2/M arrest mediated by Chk1 activation. Checkpoint abrogation, by the Wee1 kinase inhibitor adavosertib, induced glioblastoma cell lines and primary cells, DNA-damaged by UNC0379, to progress to mitosis where they died by mitotic catastrophe. Finally, UNC0379 and adavosertib synergized in restraining glioblastoma growth in a murine xenograft model, providing a strong rationale to further explore this novel pharmacological approach for adjuvant glioblastoma treatment.
- Publication
Cell Death & Disease, 2023, Vol 14, Issue 9, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-023-06167-3