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

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