EXTH-78. CRISPR/CAS9 KNOCKOUT SCREENS UNRAVEL EPIGENETIC REGULATORS AS DRUGGABLE DEPENDENCIES FOR SONIC HEDGEHOG MEDULLOBLASTOMA
نویسندگان
چکیده
Abstract Sonic hedgehog medulloblastoma (SHH-MB) is a malignant, highly heterogeneous brain tumor entity, accounting for 30% of all MBs in the pediatric population and characterized by aberrant activation canonical SHH signaling pathway. Although current therapies targeting Smoothened (Smo) have proven promising treatment approach SHH-MB patients, pre-existing or acquired resistance impedes its clinical efficacy. Therefore, novel targeted approaches that overcome mechanisms are urgently needed. Here, we performed genome-wide CRISPR/Cas9 knockout screen murine human cell line, SMB21 DAOY, respectively, order to decipher tumor-specific genetic essentialities. Our data demonstrate cells depend on key mediators pathway, such as Gli2) their proliferation, opposed DAOY cells, suggesting latter does not represent faithful model SHH-MB. Among other dependencies members epigenetic machinery Dnmt1) Smarca5). Pharmacologically, show DNMT1 inhibition efficacious at clinically relevant concentrations against Smo inhibitor- sensitive, well resistant lines. By performing RNA sequencing identified early late alterations global gene expression induced inhibition, including decreased positive regulators signaling. An additional drug unraveled synthetic lethal interactors inhibitors, validated vitro) combination treatments. Further DNA methylation profiling SMB will help define molecular basis sensitivity inhibitors Last but least, ablation combinatorial treatments using be investigated vivo) established mouse models Summarizing, our indicate potential inhibiting therapeutic avenues inhibition.
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ژورنال
عنوان ژورنال: Neuro-oncology
سال: 2022
ISSN: ['1523-5866', '1522-8517']
DOI: https://doi.org/10.1093/neuonc/noac209.876