Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer
Michael J. Lukey,
Ahmad A. Cluntun,
William P. Katt,
Miao-chong J. Lin,
Joseph E. Druso,
Sekar Ramachandran,
Jon W. Erickson,
Henry H. Le,
Zhihan-Emily Wang,
Bryant Blank,
Kai Su Greene,
Richard A. Cerione
Affiliations
Michael J. Lukey
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA
Ahmad A. Cluntun
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA
William P. Katt
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA
Miao-chong J. Lin
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA
Joseph E. Druso
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA
Sekar Ramachandran
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
Jon W. Erickson
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
Henry H. Le
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Boyce Thompson Institute, Ithaca, NY 14853, USA
Zhihan-Emily Wang
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA
Bryant Blank
Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
Kai Su Greene
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA
Richard A. Cerione
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Corresponding author
Summary: Efforts to target glutamine metabolism for cancer therapy have focused on the glutaminase isozyme GLS. The importance of the other isozyme, GLS2, in cancer has remained unclear, and it has been described as a tumor suppressor in some contexts. Here, we report that GLS2 is upregulated and essential in luminal-subtype breast tumors, which account for >70% of breast cancer incidence. We show that GLS2 expression is elevated by GATA3 in luminal-subtype cells but suppressed by promoter methylation in basal-subtype cells. Although luminal breast cancers resist GLS-selective inhibitors, we find that they can be targeted with a dual-GLS/GLS2 inhibitor. These results establish a critical role for GLS2 in mammary tumorigenesis and advance our understanding of how to target glutamine metabolism in cancer. : Lukey et al. report that basal- and luminal-subtype breast cancers employ different strategies for glutamine catabolism, impacting their sensitivity profiles to glutaminase inhibitors. Elevated GLS2 expression in luminal-subtype cancers is driven in part by GATA3. Targeting GLS2 with the pan-glutaminase inhibitor 968 inhibits luminal-subtype breast cancer cell proliferation and tumorigenesis. Keywords: breast cancer, glutaminase, glutamine metabolism GLS2, GLS, BPTES, CB-839, 968
