MEDB-28. CDK9 is a druggable mediator sustaining Myc-driven circuitry in medulloblastoma

Abstract

BACKGROUND: 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. METHODS: We used both RNAi depletion and a panel of pharmacologic agents to characterize the mechanistic and functional consequences of CDK9 inhibition in Myc-driven medulloblastoma. We used a combination of clonogenic assays and live cell imaging to assess the cytotoxic effects of CDK9 activity loss. We then performed a combination of CUT&RUN and RNA-seq to evaluate alterations to Myc binding and downstream Myc-driven transcriptional programs. Finally, we employed orthotopic xenograft models of medulloblastoma to assess CNS penetration, tolerability, and anti-tumor efficacy of lead CDK9i candidate compounds. RESULTS: Genetic or pharmacologic inhibition of CDK9 leads to a loss of Myc expression and downregulation of hallmark Myc-driven transcriptional programs. This corresponds to a loss of cell fitness, as measured by decreased proliferation and clonogenic potential. Clinically relevant CDK9 inhibitors show variable efficacy in vivo, but the CNS-penetrant zotiraciclib achieved a significant prolongation in xenograft survival. CONCLUSION: 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.