Work

OR30-08 Pharmacological Inhibitors of Glutamate Transport and Metabolism Suppress Oxidative Phosphorylation in Invasive Lobular Carcinoma

Year: 2025

Type: article

Abstract: Disclosure: D. Mobin: None. A.O. Olukoya: None. S. Bahnassy: None. S. Ranjit: None. T. Young: None. R.B. Riggins: None. Compared to other histologic subtypes of breast cancer, Invasive Lobular Carcinoma (ILC) is characterized by unique metabolic dependencies, including increased reliance on amino acid metabolism. Glutamate transport and metabolism, in particular, play a key role in promoting cancer cell growth and impairing the response to endocrine therapy (ET) in ILC. Our recent studies show the glutamate release inhibitor Riluzole enhances or restores the growth-inhibitory effects of ET in ILC preclinical models. A major fate of glutamate is conversion to alpha-ketoglutarate (aKG), essential for oxidative phosphorylation (OxPhos). Many hormone-dependent cancers, including ER+ breast cancer, are more dependent on OxPhos when they become endocrine therapy resistant (ETR). However, it remains unclear whether ETR ILC also exhibits a metabolic shift towards OxPhos, and whether targeting this dependency by pharmacological inhibitors of glutamate transport and metabolism can offer a potential therapeutic strategy. We used fluorescence lifetime imaging microscopy (FLIM), an innovative, label-free technique to measure the free vs. protein-bound state of NADH as a proxy for glycolysis vs. OxPhos, respectively. Studies were conducted in four ILC cell lines (SUM44, LCCTam, MM134, MM134-LTED) treated with three pharmacological inhibitors: Riluzole (glutamate release inhibitor); R162 (inhibitor of glutamate dehydrogenase 1, GLUD1, which converts glutamate to aKG); and erastin (inhibitor of the glutamate:cystine antiporter xCT). Like other hormone-dependent cancers, each ETR ILC cell line showed significantly increased OxPhos compared to its ET-sensitive (ETS) counterpart. Treatment with R162 significantly increased the levels of free NADH, indicative of a metabolic shift away from OxPhos and towards glycolysis, in all four ILC cell lines. Treatment with erastin significantly increased free NADH levels in ETS cells (SUM44) and the two cell lines that are resistant to Tamoxifen (LCCTam, MM134), but not in MM134-LTED, a model of aromatase inhibitor resistance. Treatment with Riluzole significantly increased free NADH levels in one ETS (SUM44) and one ETR (MM134) cell line. Altogether, we show that pharmacological inhibition of glutamate transport and metabolism can shift the metabolism of most ILC cells away from OxPhos and towards glycolysis, with the GLUD1 inhibitor R162 being the most effective. These data suggest that GLUD1 inhibition in particular may be an effective therapeutic strategy in ILC cells, regardless of their response or resistance to ET. Future studies will determine whether combination therapies of GLUD1 inhibitors with ET will have superior anti-cancer efficacy compared to ET alone. Presentation: Monday, July 14, 2025

Source: Journal of the Endocrine Society