MDB-37. CDK9 IS A DRUGGABLE MEDIATOR SUSTAINING MYC-DRIVEN TRANSCRIPTIONAL CIRCUITRY IN MEDULLOBLASTOMA

Abstract Though long recognized as a master regulator of cell proliferation across wide range cancers, Myc has proven elusive to direct therapeutic targeting. The CDK9-containing PTEFb, complexed with either BRD4 or SEC, facilitates Myc-driven transcriptional programs and is necessary for sustaining expression itself. Advances in development clinical-grade CDK9 inhibitors creates an opportunity examine this rational therapy medulloblastoma (Myc-MB). In order define the enhancer-promoter circuitry driving medulloblastoma, we performed chromosome conformation capture (Hi-C) from primary patient Myc-MB samples. Using combination CUT&RUN RNA-seq, find that treatment inhibitor zotiraciclib depletes binding activity at enhancer elements within topologically associated domain, largely abrogating output promoter. This leads decrease genome-wide concordant downregulation hallmark programs. lines are sensitive inhibition low nanomolar concentrations, loss fitness measured by decreased proliferative clonogenic potential marked induction apoptosis. Clinically relevant show variable efficacy vivo, but CNS-penetrant agents achieved significant prolongation xenograft survival. Together, these data demonstrate catalytic represents druggable vulnerability underpinning may open new avenues high-risk medulloblastomas.