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Updated: Jul 4, 2025

Heterokaryon Technique for Analysis of Cell Type-specific Localization
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Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma

Anja Deutzmann1, Delaney K Sullivan1, Renumathy Dhanasekaran1,2

  • 1Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.

Nature Communications
|February 1, 2024
PubMed

Insights

We identified genes crucial for survival in high MYC liver cancer cells, revealing nucleocytoplasmic transport as a key vulnerability. Targeting Exportin-1 (XPO1) showed promise for treating MYC-driven hepatocellular carcinoma (HCC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The MYC oncogene is frequently dysregulated in human cancers, including hepatocellular carcinoma (HCC).
  • MYC is currently considered an undruggable cancer target.
  • Identifying vulnerabilities in MYC-driven cancers is critical for therapeutic development.

Purpose of the Study:

  • To identify genes essential for the survival of MYC-high cells in HCC.
  • To uncover novel synthetic lethal interactions with MYC.
  • To investigate the therapeutic potential of targeting identified MYC-synthetic lethal interactions.

Main Methods:

  • Conducted a genome-wide CRISPR/Cas9 screen in a MYC-conditional HCC model.
  • Analyzed gene expression and survival data in murine HCC and human HCC patient cohorts.
  • Evaluated the in vivo efficacy of Exportin-1 (XPO1) inhibition in preclinical HCC models.

Main Results:

  • Discovered novel MYC synthetic lethal (MYC-SL) interactions, with nucleocytoplasmic transport emerging as a key vulnerability.
  • Found that most MYC-SL nucleocytoplasmic transport genes are upregulated in MYC-high murine HCC and linked to poor patient survival.
  • Demonstrated significant tumor regression and growth inhibition by targeting XPO1 in vivo in HCC models.
  • Observed that XPO1's prognostic significance in HCC is restricted to patients with high MYC activity.

Conclusions:

  • Nucleocytoplasmic transport represents a critical dependency and potential therapeutic target in MYC-driven HCC.
  • XPO1 inhibition shows therapeutic promise for hepatocellular carcinoma with high MYC expression.
  • MYC may broadly regulate and necessitate altered nucleocytoplasmic transport gene expression for tumorigenesis.

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