A peptide encoded by upstream open reading frame of <i>MYC</i> binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice.

Abstract

MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant <i>MYC</i> transcript encodes a 114-amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) <i>MPEP</i>. Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor-bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a <i>MYC</i>-associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.