eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

Boyer, Jacob A, Rosen, Ezra Y, Sharma, Malvika, Dorso, Madeline A, Mai, Nicholas, Amor, Corina, Reiter, Jason M, Kannan, Ram, Gadal, Sunyana, Xu, Jianing, Miele, Matthew, Li, Zhuoning, Chen, Xiaoping, Chang, Qing, Pareja, Fresia, Worland, Stephan, Warner, Douglas, Sperry, Sam, Chiang, Gary G, Thompson, Peggy A, Yang, Guangli, Ouerfelli, Ouathek, Drilon, Alexander, de Stanchina, Elisa, Wendel, Hans-Guido, Chandarlapaty, Sarat, Rosen, Neal (July 2025) eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 122 (30). e2424286122. ISSN 0027-8424

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Abstract

Most breast cancers depend on hormone-stimulated estrogen receptor alpha (ER) activity and are sensitive to ER inhibition. Resistance can arise from activating mutations in the gene encoding ER (ESR1) or from reactivation of downstream targets. Newer ER antagonists occasionally show efficacy but are largely ineffective as single agents in the long term. Here, we show that ER translation is eIF4E/cap-independent yet sensitive to inhibitors of the translation initiation factor eIF4A. EIF4A inhibition reduces the expression of ER and cell cycle regulators such as cyclin D1. This leads to growth suppression in ligand-independent breast cancer models, including those driven by ER mutants and fusion proteins. Efficacy is enhanced by adding the ER degrader, fulvestrant. The combination further lowers ER expression and blocks tumor growth in vitro and in vivo. In an early clinical trial (NCT04092673), the eIF4A inhibitor zotatifin was combined with either fulvestrant or fulvestrant plus CDK4 inhibitor, abemaciclib, in patients with acquired resistance to these agents. Multiple clinical responses including a handful of durable regressions were observed, with little toxicity. Thus, eIF4A inhibition could be useful for treating ER+ breast cancer resistant to other modalities.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > breast cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Amor, Corina
Communities:	CSHL labs > Amor lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	29 July 2025
Date Deposited:	24 Jul 2025 17:59
Last Modified:	24 Jul 2025 17:59
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41917

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