Super Elongation Complex as a Targetable Dependency in Diffuse Midline Glioma
Nathan Dahl, Etienne Danis, Ilango Balakrishnan, Dong Wang, Angela Pierce, Faye Walker, Ahmed Gilani, Natalie J. Serkova, Krishna Madhavan, Susan Fosmire, Adam L. Green, Nicholas K. Foreman, Sujatha Venkataraman, Rajeev Vibhakar
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.