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

Authors

Anja Deutzmann, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
Delaney K. Sullivan, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
Renumathy Dhanasekaran, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
Wei Li, Center for Genetic Medicine Research, Children's National Hospital, Washington, DC, 20012, USA.
Xinyu Chen, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
Ling Tong, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
Wadie D. Mahauad-Fernandez, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
John Bell, Stanford Genome Technology Center, Stanford University, Stanford, CA, 94305, USA.
Adriane Mosley, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
Angela N. Koehler, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Yulin Li, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA. yli@houstonmethodist.org.
Dean W. Felsher, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA. dfelsher@stanford.edu.

Document Type

Journal Article

Publication Date

2-1-2024

Journal

Nature communications

Volume

15

Issue

1

DOI

10.1038/s41467-024-45128-y

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 MYC but not MYC 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 MYC 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.

APA Citation

Deutzmann, Anja; Sullivan, Delaney K.; Dhanasekaran, Renumathy; Li, Wei; Chen, Xinyu; Tong, Ling; Mahauad-Fernandez, Wadie D.; Bell, John; Mosley, Adriane; Koehler, Angela N.; Li, Yulin; and Felsher, Dean W., "Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma" (2024). GW Authored Works. Paper 4410.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4410

Department

Genomics and Precision Medicine