Significance H3K27M mutant DMGs including DIPGs are deadly childhood brain cancers. More than 250 clinical trials over the past 50 y have failed to yield effective therapies. This underscores the… Click to show full abstract
Significance H3K27M mutant DMGs including DIPGs are deadly childhood brain cancers. More than 250 clinical trials over the past 50 y have failed to yield effective therapies. This underscores the importance of understanding the biology of these tumors to develop efficacious therapies. Because H3K27M mutations suppress PRC2 function, and PRC2 opposes the BAF form of the SWI/SNF complex, we targeted key members of the SWI/SNF complex as a potential therapy. We demonstrate that a PROTAC tool compound AU-15330 that simultaneously degrades the ATPases SMARCA4 and SMARCA2 and PBRM1 selectively kills H3.3K27M but not H3WT glioma cell lines. Our studies suggest that targeting key components of the SWI/SNF complex can provide a potent therapy for these lethal pediatric brain cancers.
               
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