eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (27)
Jacob A. Boyer
Ludwig Institute for Cancer Research, Princeton Branch, Princeton University
Ezra Y. Rosen
Department of Medicine, Memorial Sloan Kettering Cancer Center
Malvika Sharma
Program in Molecular Pharmacology, Department of Medicine, Memorial Sloan Kettering Cancer Center
Madeline A. Dorso
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Nicholas Mai
Department of Medicine, Memorial Sloan Kettering Cancer Center
Corina Amor
Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center
Jason M. Reiter
Program in Molecular Pharmacology, Department of Medicine, Memorial Sloan Kettering Cancer Center
Ram Kannan
Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Sunyana Gadal
Program in Molecular Pharmacology, Department of Medicine, Memorial Sloan Kettering Cancer Center
Jianing Xu
Program in Molecular Pharmacology, Department of Medicine, Memorial Sloan Kettering Cancer Center
Matthew Miele
Microchemistry and Proteomics Core Facility, Memorial Sloan Kettering Cancer Center
Zhuoning Li
Xiaoping Chen
Qing Chang
Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center
Fresia Pareja
Stephan Worland
Department of Cancer Biology, eFFECTOR Therapeutics, Inc.
Douglas Warner
Department of Cancer Biology, eFFECTOR Therapeutics, Inc.
Sam Sperry
Department of Cancer Biology, eFFECTOR Therapeutics, Inc.
Gary G. Chiang
Department of Cancer Biology, eFFECTOR Therapeutics, Inc.
Peggy A. Thompson
Department of Cancer Biology, eFFECTOR Therapeutics, Inc.
Guangli Yang
Ouathek Ouerfelli
Alexander Drilon
Department of Medicine, Memorial Sloan Kettering Cancer Center
Elisa de Stanchina
Hans-Guido Wendel
Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Sarat Chandarlapaty
Neal Rosen
Program in Molecular Pharmacology, Department of Medicine, Memorial Sloan Kettering Cancer Center