Yasuaki Uemoto , Chang-Ching A. Lin , Bingnan Wang , Dan Ye , Yisheng V. Fang , Emmanuel Bikorimana , Fabiana Napolitano , Maria Rosario Chica-Parrado , Cheung Li , Saurabh Mendiratta , Chuo Chen , Ariella B. Hanker , Carlos L. Arteaga
{"title":"Selective degradation of FGFR1/2 overcomes antiestrogen resistance in ER+ breast cancer with FGFR1/2 alterations","authors":"Yasuaki Uemoto , Chang-Ching A. Lin , Bingnan Wang , Dan Ye , Yisheng V. Fang , Emmanuel Bikorimana , Fabiana Napolitano , Maria Rosario Chica-Parrado , Cheung Li , Saurabh Mendiratta , Chuo Chen , Ariella B. Hanker , Carlos L. Arteaga","doi":"10.1016/j.canlet.2025.217668","DOIUrl":null,"url":null,"abstract":"<div><div><em>FGFR1</em> amplification and <em>FGFR1/2</em> activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring <em>FGFR1/2</em> somatic alterations. Treatment of ER+/<em>FGFR1</em>-amplified breast cancer cells and patient-derived xenografts with DGY-09-192 resulted in sustained degradation of FGFR1 in a proteasome-dependent manner and suppressed downstream signal transduction. The combination of DGY-09-192 and the ERα degrader fulvestrant resulted in complete cell growth arrest and tumor regression of ER+/<em>FGFR1</em>-amplified patients-derived xenografts. In addition, we tested the effect of DGY-09-192 on breast cancer cells expressing <em>FGFR1</em><sup><em>N546K</em></sup> and <em>FGFR2</em><sup><em>K659E</em></sup> hotspot kinase domain mutations as well as ER-negative breast cancer cells harboring <em>FGFR2</em> gene amplification. Treatment with DGY-09-192 resulted in the degradation of mutant FGFR1/2 and blocked mutant receptor-induced signal transduction and antiestrogen resistance. Collectively, our study suggests that degradation of FGFR1/2, in combination with antiestrogens, can be leveraged as a therapeutic strategy in ER + breast cancers harboring <em>FGFR1/2</em> driver alterations.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217668"},"PeriodicalIF":9.1000,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0304383525002344","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring FGFR1/2 somatic alterations. Treatment of ER+/FGFR1-amplified breast cancer cells and patient-derived xenografts with DGY-09-192 resulted in sustained degradation of FGFR1 in a proteasome-dependent manner and suppressed downstream signal transduction. The combination of DGY-09-192 and the ERα degrader fulvestrant resulted in complete cell growth arrest and tumor regression of ER+/FGFR1-amplified patients-derived xenografts. In addition, we tested the effect of DGY-09-192 on breast cancer cells expressing FGFR1N546K and FGFR2K659E hotspot kinase domain mutations as well as ER-negative breast cancer cells harboring FGFR2 gene amplification. Treatment with DGY-09-192 resulted in the degradation of mutant FGFR1/2 and blocked mutant receptor-induced signal transduction and antiestrogen resistance. Collectively, our study suggests that degradation of FGFR1/2, in combination with antiestrogens, can be leveraged as a therapeutic strategy in ER + breast cancers harboring FGFR1/2 driver alterations.
期刊介绍:
Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research.
Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy.
By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.