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Blockade of insulin signaling cooperates with PI3K inhibitors to suppress MYCN pediatric high grade glioma growth [RNA-seq1]

ABSTRACT: MYCN amplification is an adverse genomic feature of several childhood malignancies and has been a challenging therapeutic target. We modeled MYCN amplified high grade gliomas (HGG-MYCN) and, with integrative omics, revealed activation of the PI3K-mTOR signaling pathway. Inhibition of PI3K-mTOR signaling attenuates MYCN protein and reduces tumor growth. Persistent inhibition of PI3K-mTOR results in rebounding of MYCN protein to levels comparable to that of drug naïve cells, indicating that these cells develop resistance. Characterization of resistant cells demonstrates hyperactivation of the insulin and insulin growth factor 1 receptors. We demonstrate that PI3K-mTOR inhibition in combination with dietary restriction, diabetic therapies or early clinical trial agents targeting insulin receptors are synergistic and sustain MYCN suppression. Forced overexpression of nondegradable MYCN completely blocks the efficacy of dual treatments and rescues tumor growth. These findings have immediate implications for clinical trials using PI3K-mTOR inhibitors and reveal novel therapeutic paradigms for tumors expressing MYCN.

ORGANISM(S): Mus musculus

PROVIDER: GSE289649 | GEO | 2026/03/21

REPOSITORIES: GEO

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