MYCN drives pediatric glioma transformation from neural progenitors and creates distinct therapeutic vulnerabilities

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.