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

Ayodeji O Olukoya; Hillary Stires; Shaymaa Bahnassy; Sonali Persaud; Yanira Guerra; Suman Ranjit; Shihong Ma; M Idalia Cruz; Carlos Benitez; Aaron M Rozeboom; Hannah Ceuleers; Deborah L Berry; Britta M Jacobsen; Ganesh V Raj; Rebecca B Riggins

doi:10.1210/jendso/bvad117

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

J Endocr Soc. 2023 Sep 15;7(10):bvad117. doi: 10.1210/jendso/bvad117. eCollection 2023 Aug 28.

Authors

Affiliations

¹ Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
² Department of Biochemistry, Georgetown University, Washington, DC 20057, USA.
³ Departments of Urology and Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
⁴ Department of Pathology, University of Colorado Anschutz Medical Campus, Denver, CO 80045, USA.

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 antitumor 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 prosurvival 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.

Conclusion: Riluzole may offer therapeutic benefits in diverse ER+ breast cancers, including lobular breast cancer.

Keywords: estrogen receptor; fulvestrant; invasive lobular breast cancer; riluzole.

Grants and funding

T32 CA009686/CA/NCI NIH HHS/United States