Open AccessTargeting MYC-driven replication stress in medulloblastoma with AZD1775 and gemcitabine
Author(s) -
Daniel C. Moreira,
Sujatha Venkataraman,
Apurva Subramanian,
John DeSisto,
Ilango Balakrishnan,
Eric Prince,
Angela Pierce,
Andrea M. Griesinger,
Adam Green,
Charles Eberhardt,
Nicholas Foreman,
Rajeev Vibhakar
Publication year - 2020
Publication title -
journal of neuro-oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.256
H-Index - 114
eISSN - 1573-7373
pISSN - 0167-594X
DOI - 10.1007/s11060-020-03457-0
Subject(s) - medulloblastoma , gemcitabine , wee1 , cancer research , in vivo , cell cycle , apoptosis , cell cycle checkpoint , ex vivo , biology , medicine , cancer , genetics , cyclin dependent kinase 1
MYC-driven medulloblastomas are highly aggressive childhood tumors with dismal outcomes and a lack of new treatment paradigms. We identified that targeting replication stress through WEE1 inhibition to suppress the S-phase replication checkpoint, combined with the attenuation of nucleotide synthesis with gemcitabine, is an effective strategy to induce apoptosis in MYC-driven medulloblastoma that could be rapidly translated into early phase clinical trials in children. Attenuation of replication stress is a key component of MYC-driven oncogenesis. Previous studies revealed a vulnerability in MYC medulloblastoma through WEE1 inhibition. Here, we focused on elucidating combinations of agents to synergize with WEE1 inhibition and drive replication stress toward cell death.