Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Abstract

BackgroundResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, Riluzole has shown anti-tumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. In several (but not all) of these studies, Riluzole-mediated growth inhibition is attributed to increased expression of metabotropic glutamate receptors (mGluRs, GRMs). We recently reported that acquisition of Tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by Riluzole.MethodsIn the current study, we tested the ability of Riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.ResultsSingle-agent Riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). In an invasive lobular, endocrine resistant model, Riluzole induced apoptosis and reduced phosphorylation of multiple pro-survival signaling molecules, including Akt/mTOR, CREB, and Src/Fak family kinases. Riluzole in combination with either Fulvestrant or 4-hydroxytamoxifen additively or synergistically suppressed ER+ breast cancer cell growth in vitro. The combination of Riluzole plus Fulvestrant significantly reduced proliferation in primary breast tumor explant cultures, and inhibited HCI-013EI xenograft growth in vivo significantly earlier than Fulvestrant alone.ConclusionsThese findings suggest Riluzole combined with endocrine therapy may offer therapeutic benefit in diverse ER+ breast cancers, including lobular breast cancer.

WNT4 regulates cellular metabolism via intracellular activity at the mitochondria in breast and gynecologic cancers

“…Similarly, though ILC are less FDG-avid, the impact of therapy and disease progression on ILC metabolism (and thus FDG avidity) has not been extensively explored outside of anti-estrogen resistant cell line variants. Stires et al reported that while single agent riluzole did not impact growth of ILC PDX HCI-013EI (an estrogen-independent outgrowth of parental HCI-013), combining riluzole with fulvestrant delayed tumor growth longer than fulvestrant alone, supporting that glutamate metabolism is important in ILC tumor response to fulvestrant in vivo [18]. Further, ILC PDX HCI-013 showed intra-tumor metabolic heterogeneity, which was greater in the endocrine resistant HCI-013EI [46].…”

“…Tumor metabolite tracing, PET-CT studies pairing FDG with other tracers (e.g. 18 F-fluoroestradiol [8,12]), and alternative imaging approaches [47], may facilitate further study of ILC tumor metabolism and metabolic remodeling during therapy response and resistance, and disease progression.…”

“…The limited avidity for FDG in PET-CT imaging strongly suggests that ILC tumors preferentially utilize fuels other than glucose, such as amino acids and/or fatty acids, in particular in the context of advanced anti-estrogen-resistant ILC. Studies from the Riggins Laboratory have shown that ILC cell lines are uniquely sensitive to inhibition of glutamate transport using riluzole, especially in combination with ER inhibition [17, 18]. Similarly, in a panel of breast tumor explant cultures (n=5) including one ILC, the ILC was unique in being growth suppressed by single agent riluzole and combined riluzole + fulvestrant [18].…”

“…In parallel, this study observed that genes differentially expressed in Luminal A ILC vs Luminal A IDC (n=1360) were strongly enriched for metabolic pathways, with overall reduced expression of genes involved in glucose metabolism in ILC vs IDC. Reduced glucose metabolism is also observed in clinical ILC tumor imaging -ILC tumors have on average ~40% reduced glucose uptake versus IDC in 18 F-fluorodeoxyglucose (FDG)/PET-CT imaging [7][8][9][10][11][12]. ILC tumors with no detectable FDG uptake are common, especially in metastatic ILC [8,12,13].…”

“…GDH/ GLUD1 , SDHA) compared to IDC [14]. ILC tumors also show differential expression of lipid metabolism-related proteins [15], and accordingly, studies with anti-estrogen resistant ILC models identify increased lipid and glutamate metabolism as critical to the resistant phenotype [16–18]. Taken together, these observations suggest that ER+ ILC cells and tumors have a distinct metabolic phenotype compared to other breast cancers, including reduced glucose uptake and metabolism.…”