Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer

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. [Display omitted] •Basal- and luminal-subtype breast cancers express GLS and GLS2, respectively•GLS2 expression in breast cancer is regulated by promoter methylation and GATA3•GLS2 supports proliferation and tumorigenesis in luminal-subtype breast cancers•968 inhibits GLS2 to suppress luminal-subtype breast cancer growth 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.