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; Dean W Felsher

doi:10.1038/s41467-024-45128-y

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

Nat Commun. 2024 Feb 1;15(1):963. doi: 10.1038/s41467-024-45128-y.

Authors

Anja Deutzmann¹, Delaney K Sullivan¹, Renumathy Dhanasekaran^{1

2}, Wei Li^{3

4}, Xinyu Chen¹, Ling Tong¹, Wadie D Mahauad-Fernandez¹, John Bell⁵, Adriane Mosley¹, Angela N Koehler^{6

7

8

9}, Yulin Li^#^{10

11}, Dean W Felsher^#^{12

13

14}

Affiliations

¹ Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
² Division of Gastroenterology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
³ Center for Genetic Medicine Research, Children's National Hospital, Washington, DC, 20012, USA.
⁴ Department of Genomics and Precision Medicine, George Washington University, Washington, DC, 20012, USA.
⁵ Stanford Genome Technology Center, Stanford University, Stanford, CA, 94305, USA.
⁶ Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
⁷ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
⁸ Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
¹⁰ Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA. yli@houstonmethodist.org.
¹¹ Institute for Academic Medicine, Houston Methodist and Weill Cornell Medical College, Houston, TX, 77030, USA. yli@houstonmethodist.org.
¹² Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA. dfelsher@stanford.edu.
¹³ Department of Pathology, Stanford University, Stanford, CA, 94305, USA. dfelsher@stanford.edu.
¹⁴ Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA. dfelsher@stanford.edu.

^# Contributed equally.

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^high but not MYC^low 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^high 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.

MeSH terms

Animals
Carcinogenesis / genetics
Carcinoma, Hepatocellular* / metabolism
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Gene Expression Regulation, Neoplastic
Genes, myc
Humans
Liver Neoplasms* / metabolism
Mice
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism

Substances

Proto-Oncogene Proteins c-myc

Abstract

MeSH terms

Substances

Grants and funding