Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma

Anja Deutzmann, Delaney K. Sullivan, Renumathy Dhanasekaran, Wei Li, Xinyu Chen, Ling Tong, Wadie D. Mahauad-Fernandez, John Bell, Adriane Mosley, Angela N. Koehler, Yulin Li () and Dean W. Felsher ()
Additional contact information
Anja Deutzmann: Stanford University
Delaney K. Sullivan: Stanford University
Renumathy Dhanasekaran: Stanford University
Wei Li: Center for Genetic Medicine Research, Children’s National Hospital
Xinyu Chen: Stanford University
Ling Tong: Stanford University
Wadie D. Mahauad-Fernandez: Stanford University
John Bell: Stanford University
Adriane Mosley: Stanford University
Angela N. Koehler: Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology
Yulin Li: Stanford University
Dean W. Felsher: Stanford University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively identify genes essential for survival of MYChigh but not MYClow cells by a CRISPR/Cas9 genome-wide screen in a MYC-conditional HCC model. Our screen uncovers novel MYC synthetic lethal (MYC-SL) interactions and identifies most MYC-SL genes described previously. In particular, the screen reveals nucleocytoplasmic transport to be a MYC-SL interaction. We show that the majority of MYC-SL nucleocytoplasmic transport genes are upregulated in MYChigh murine HCC and are associated with poor survival in HCC patients. Inhibiting Exportin-1 (XPO1) in vivo induces marked tumor regression in an autochthonous MYC-transgenic HCC model and inhibits tumor growth in HCC patient-derived xenografts. XPO1 expression is associated with poor prognosis only in HCC patients with high MYC activity. We infer that MYC may generally regulate and require altered expression of nucleocytoplasmic transport genes for tumorigenesis.

Date: 2024
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DOI: 10.1038/s41467-024-45128-y

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