eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer Journal Article
| Authors: | Boyer, J. A.; Rosen, E. Y.; Sharma, M.; Dorso, M. A.; Mai, N.; Amor, C.; Reiter, J. M.; Kannan, R.; Gadal, S.; Xu, J.; Miele, M.; Li, Z.; Chen, X.; Chang, Q.; Pareja, F.; Worland, S.; Warner, D.; Sperry, S.; Chiang, G. G.; Thompson, P. A.; Yang, G.; Ouerfelli, O.; Drilon, A.; de Stanchina, E.; Wendel, H. G.; Chandarlapaty, S.; Rosen, N. |
| Article Title: | 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. © 2025 Elsevier B.V., All rights reserved. |
| Keywords: | immunohistochemistry; controlled study; human tissue; protein expression; unclassified drug; gene mutation; human cell; genetics; flow cytometry; cell proliferation; mass spectrometry; mouse; phenotype; animal; cytology; metabolism; animals; mice; gene; metastasis; reverse transcription polymerase chain reaction; apoptosis; phase 2 clinical trial; breast cancer; gene expression; cell growth; tumor volume; cohort analysis; antineoplastic activity; drug effect; drug screening; pathology; xenograft model antitumor assays; cell line, tumor; breast neoplasms; gene expression regulation; gene expression regulation, neoplastic; genetic transfection; messenger rna; protein synthesis; breast tumor; tumor cell line; initiation factor 4e; initiation factor 4e binding protein 1; protein biosynthesis; tamoxifen; translation; 3' untranslated region; phase 1 clinical trial; estrogen receptor; progesterone receptor; drug therapy; trastuzumab; cyclin d1; half life time; estradiol; initiation factor 4a; mcf-7 cells; cyclin dependent kinase 4; argonaute 1 protein; fulvestrant; polyacrylamide gel electrophoresis; cyclin dependent kinase 6; genetic transcription and translation; beta actin; protein kinase b beta; transcription factor sox9; estrogen receptor alpha; gene ontology; liquid chromatography-mass spectrometry; silvestrol; eukaryotic initiation factor-4a; advanced breast cancer; humans; human; female; article; eif4a; gene expression assay; protein p56; cell viability assay; luciferase assay; ic50; abemaciclib; mcf-7 cell line; hek293t cell line; cell proliferation assay; chemiluminescence immunoassay; rocaglamide a; chromatin immunoprecipitation sequencing; zotatifin; oncogene fusion protein; camizestrant; esr1 protein, human; graphpad prism 8.0; eukaryotic translation initiation factor 4g; mcf7/lcc1 cell line |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 122 |
| Issue: | 30 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2025-07-29 |
| Start Page: | e2424286122 |
| Language: | English |
| DOI: | 10.1073/pnas.2424286122 |
| PUBMED: | 40690678 |
| PROVIDER: | scopus |
| PMCID: | PMC12318197 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding authors are Sarat Chandarlapaty and Neal Rosen -- Source: Scopus |
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