Cargando…

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

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 mechanis...

Descripción completa

Detalles Bibliográficos
Autores principales: Olukoya, Ayodeji O, Stires, Hillary, Bahnassy, Shaymaa, Persaud, Sonali, Guerra, Yanira, Ranjit, Suman, Ma, Shihong, Cruz, M Idalia, Benitez, Carlos, Rozeboom, Aaron M, Ceuleers, Hannah, Berry, Deborah L, Jacobsen, Britta M, Raj, Ganesh V, Riggins, Rebecca B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10521904/
https://www.ncbi.nlm.nih.gov/pubmed/37766843
http://dx.doi.org/10.1210/jendso/bvad117
Descripción
Sumario: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.