MYCN drives pediatric glioma transformation from neural progenitors and creates distinct therapeutic vulnerabilities
Taylor A Gatesman1, Srinidhi Varadharajan2, Brenden J Johnson3
1Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; John G Rangos Sr. Research Center, Children's Hospital of Pittsburgh, PA, USA; Department of Cellular and Molecular Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; The Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Abstract:
MYCN functions as a developmental oncogene, but its role in pediatric high-grade gliomas (pHGGs) remains unclear. In co-operation with Trp53 and Pten loss, MYCN initiates tumorigenesis and establishes an origin for MYCN-driven pHGGs. This transformation creates a vulnerability to PI3K and mTOR inhibition. However, prolonged treatment drives adaptive resistance through MYCN protein rebound, mediated by the attenuation of IGFBP5 and the induction of insulin-like growth factor 2. Although insulin pathway feedback has been implicated in resistance to PI3K targeted therapies, MYCN emerges as the central node of this adaptive program. Resistance can be overcame by sustained MYCN suppression using PI3K and mTOR inhibitors, combined with insulin-like growth factor 1 receptor and insulin receptor inhibitors or dietary intervention. A degradation-resistant MYCN isoform abolishes this response, establishing MYCN as both an initiating oncogene and a resistance driver and revealing a mechanistically defined therapeutic vulnerability.
Insights
MYCN drives pediatric high-grade gliomas and resistance to targeted therapies. Sustained MYCN suppression, combined with other inhibitors or dietary changes, can overcome this resistance.
Area of Science:
- Oncology
- Molecular Biology
- Developmental Biology
Background:
- The role of MYCN in pediatric high-grade gliomas (pHGGs) is not fully understood.
- MYCN acts as a developmental oncogene, potentially initiating tumorigenesis in collaboration with Trp53 and Pten loss.
Purpose of the Study:
- To elucidate the function of MYCN in initiating pHGGs.
- To investigate the mechanisms of therapeutic resistance in MYCN-driven pHGGs.
- To identify strategies for overcoming resistance to PI3K and mTOR inhibition.
Main Methods:
- Investigated MYCN's role in pHGG initiation and resistance mechanisms.
- Analyzed adaptive resistance pathways involving MYCN protein rebound, IGFBP5 attenuation, and IGF2 induction.
- Evaluated therapeutic strategies including PI3K/mTOR inhibitors, IGF1R/IR inhibitors, and dietary interventions.
Main Results:
- MYCN, alongside Trp53 and Pten loss, initiates MYCN-driven pHGGs, creating vulnerability to PI3K/mTOR inhibition.
- Prolonged treatment leads to adaptive resistance via MYCN protein rebound, mediated by IGFBP5 and IGF2.
- MYCN is identified as the central regulator of this adaptive resistance program.
Conclusions:
- MYCN is a critical oncogene in pHGG initiation and a key driver of therapeutic resistance.
- Sustained MYCN suppression through combination therapies (PI3K/mTOR inhibitors, IGF1R/IR inhibitors) or dietary intervention can overcome resistance.
- Targeting MYCN and its adaptive pathways presents a mechanistically defined therapeutic vulnerability in pHGGs.
