Super Elongation Complex as a Targetable Dependency in Diffuse Midline Glioma

Abstract

Histone 3 gene mutations are the eponymous drivers in diffuse midline gliomas (DMGs), aggressive pediatric brain cancers for which no curative therapy currently exists. These recurrent oncohistones induce a global loss of repressive H3K27me3 residues and broad epigenetic dysregulation. In order to identify therapeutically targetable dependencies within this disease context, we performed an RNAi screen targeting epigenetic/chromatin-associated genes in patient-derived DMG cultures. This identified AFF4, the scaffold protein of the super elongation complex (SEC), as a molecular dependency in DMG. Interrogation of SEC function demonstrates a key role for maintaining clonogenic potential while promoting self-renewal of tumor stem cells. Small-molecule inhibition of SEC using clinically relevant CDK9 inhibitors restores regulatory RNA polymerase II pausing, promotes cellular differentiation, and leads to potent anti-tumor effect both in vitro and in patient-derived xenograft models. These studies present a rationale for further exploration of SEC inhibition as a promising therapeutic approach to this intractable disease.

Keywords: AFF4; AZD4573; CDK9; DIPG; DMG; SEC; atuveciclib; diffuse intrinsic pontine glioma; diffuse midline glioma; super elongation complex.