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Synergistic RAS-MAPK and AKT Activation in MYC-Driven Tumors via Adjacent PVT1 Rearrangements

Ashutosh Tiwari1, Utkarsha Paithane1, Jordan Friedlein1

  • 1Cancer Genome and Epigenetics Program, NCI Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Biorxiv : the Preprint Server for Biology
|March 3, 2025
PubMed

Insights

Rearrangements in the PVT1 gene create Firefox (FFX) and lose Honeybadger (HNB). FFX activates cancer pathways, while HNB suppresses them, explaining MYC+ cancer aggressiveness and offering therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • MYC-driven (MYC+) cancers are aggressive, with MYC dysregulation being a key event.
  • Overexpression of MYC alone is insufficient for cancer development.
  • Plasmocytoma Variant Translocation 1 (PVT1), a long non-coding RNA (lncRNA) near MYC, is frequently rearranged in MYC+ cancers.

Purpose of the Study:

  • To investigate the functional consequences of genomic rearrangements at the PVT1 locus in MYC+ cancers.
  • To identify novel peptides encoded by PVT1 and their roles in cancer progression.
  • To elucidate the mechanism by which PVT1 rearrangements synergize with MYC to drive cancer aggressiveness.

Main Methods:

  • Analysis of genomic rearrangements at the PVT1 locus.
  • Identification and characterization of novel peptides (Firefox and Honeybadger) derived from PVT1.
  • Investigation of signaling pathways (AKT, mTORC1, RAS/MAPK) modulated by these peptides.
  • Assessment of MYC stability and phosphorylation.

Main Results:

  • Translocation at PVT1 leads to 5'-PVT1 enrichment and 3'-PVT1 loss.
  • The retained 5' region generates circular RNA (CircPVT1) encoding Firefox (FFX), which augments AKT signaling and synergizes with MYC and mTORC1.
  • The lost 3' region encodes tumor-suppressing Honeybadger (HNB), which interacts with KRAS and inhibits its effectors; loss of HNB activates RAS/MAPK signaling and enhances MYC stability.
  • PVT1 acts as a critical node synchronizing MYC, AKT, and RAS-MAPK activities.

Conclusions:

  • PVT1 rearrangements activate oncogenic pathways that cooperate with MYC, increasing the aggressiveness of MYC+ cancers.
  • The balance between FFX and HNB peptides derived from PVT1 is crucial in regulating cancer progression.
  • These findings offer potential therapeutic targets for MYC+ cancers.

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