Riluzole Suppresses Growth and Enhances Response to Endocrine Therapy in ER+ Breast Cancer

Abstract

Background Resistance 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. We previously reported that the 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. Methods 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. Results Single-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). Riluzole induced apoptosis and ferroptosis and reduced phosphorylation of multiple pro-survival signaling molecules, including Akt/mTOR, CREB, and Fak/Src family kinases. Riluzole, in combination with either Fulvestrant or 4-hydroxytamoxifen, additively suppressed ER + breast cancer cell growth in vitro. Single-agent Riluzole significantly inhibited HCI-013EI patient-derived xenograft growth in vivo, and the combination of Riluzole plus Fulvestrant significantly reduced proliferation in ex vivo primary breast tumor explant cultures. Conclusions Riluzole may offer therapeutic benefits in diverse ER + breast cancers, including lobular breast cancer.

Ranolazine: a potential anti-metastatic drug targeting voltage-gated sodium channels

“…Thus, in combination with either fulvestrant or 4-hydroxytamoxifen, riluzole additively suppressed oestrogen receptor positive breast cancer cell growth in vitro. In ex vivo primary breast tumour explant cultures, riluzole significantly enhanced the anti-proliferative effect of fulvestrant [ 54 ]. Cisplatin resistance in colorectal cancer cells was shown earlier to be overcome, at least partially, by treatment with riluzole [ 55 ].…”

A Path to Precision Metabolic Treatment in Breast Cancer: Riluzole, Glutamate Signaling, and Invasive Lobular Carcinoma

“…Recent studies indicate that PET/CT imaging with 18 F-fluorodeoxyglucose (FDG), a mainstay in managing metastatic breast cancer, has limited utility in metastatic ILC [ 1 ]. A recent study by Olukoya and colleagues [ 2 ] offers insight toward leveraging this clinical liability into therapeutic opportunity.…”