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Published on: September 13, 2022
Super Elongation Complex as a Targetable Dependency in Diffuse Midline Glioma
Nathan A Dahl1, Etienne Danis2, Ilango Balakrishnan2
1Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, CO, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA.
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.
Insights
Histone 3 mutations drive pediatric brain cancer diffuse midline gliomas (DMGs). Targeting the super elongation complex (SEC) with CDK9 inhibitors shows potent anti-tumor effects by restoring gene regulation and promoting cell differentiation.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Diffuse midline gliomas (DMGs) are aggressive pediatric brain cancers driven by Histone 3 gene mutations.
- These mutations cause widespread epigenetic dysregulation, including loss of H3K27me3 repressive marks.
- Current therapies for DMGs are ineffective, necessitating novel therapeutic strategies.
Purpose of the Study:
- To identify therapeutically targetable dependencies in DMG by screening epigenetic and chromatin-associated genes.
- To investigate the role of the super elongation complex (SEC) in DMG pathogenesis.
- To evaluate the efficacy of SEC inhibition as a potential therapeutic approach for DMGs.
Main Methods:
- Performed an RNAi screen targeting epigenetic/chromatin-associated genes in patient-derived DMG cultures.
- Interrogated the function of AFF4 and the SEC in maintaining tumor stem cell properties.
- Utilized clinically relevant CDK9 inhibitors to target SEC activity in vitro and in vivo.
Main Results:
- Identified AFF4, a scaffold protein of the SEC, as a molecular dependency in DMG.
- Demonstrated that SEC maintains clonogenic potential and self-renewal of DMG stem cells.
- Showed that SEC inhibition with CDK9 inhibitors restores RNA polymerase II pausing, promotes differentiation, and exerts potent anti-tumor effects in vitro and in xenograft models.
Conclusions:
- The super elongation complex (SEC) is a critical dependency in diffuse midline gliomas.
- Inhibition of SEC using CDK9 inhibitors represents a promising therapeutic strategy for pediatric brain cancers like DMGs.
- Targeting SEC offers a novel approach to overcome treatment resistance in intractable pediatric brain tumors.
