Selective degradation of FGFR1/2 overcomes antiestrogen resistance in ER+ breast cancer with FGFR1/2 alterations

IF 9.1 1区 医学 Q1 ONCOLOGY
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 ,&nbsp;Chang-Ching A. Lin ,&nbsp;Bingnan Wang ,&nbsp;Dan Ye ,&nbsp;Yisheng V. Fang ,&nbsp;Emmanuel Bikorimana ,&nbsp;Fabiana Napolitano ,&nbsp;Maria Rosario Chica-Parrado ,&nbsp;Cheung Li ,&nbsp;Saurabh Mendiratta ,&nbsp;Chuo Chen ,&nbsp;Ariella B. Hanker ,&nbsp;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.
FGFR1/2的选择性降解克服了雌激素受体阳性乳腺癌中FGFR1/2改变的抗雌激素抵抗。
FGFR1扩增和FGFR1/2激活突变与雌激素受体阳性(ER+)乳腺癌的抗雌激素抗性相关。然而,目前还没有批准的fgfr1靶向治疗含有这些改变的乳腺癌。在这项研究中,我们使用蛋白水解靶向嵌合体(PROTAC) DGY-09-192研究了FGFR1/2的选择性降解,作为一种新的治疗策略,用于ER+乳腺癌中含有FGFR1/2体细胞改变。用DGY-09-192治疗ER+/FGFR1扩增的乳腺癌细胞和患者来源的异种移植物可导致FGFR1以蛋白酶体依赖的方式持续降解,并抑制下游信号转导。DGY-09-192与ERα降降剂氟维司汀联合使用可导致ER+/ fgfr1扩增患者来源的异种移植物的完全细胞生长停止和肿瘤消退。此外,我们还测试了DGY-09-192对表达FGFR1N546K和FGFR2K659E热点激酶结构域突变的乳腺癌细胞以及携带FGFR2基因扩增的er阴性乳腺癌细胞的影响。DGY-09-192可降解突变体FGFR1/2,阻断突变体受体诱导的信号转导和抗雌激素抗性。总的来说,我们的研究表明,FGFR1/2的降解与抗雌激素结合,可以作为一种治疗策略,用于治疗含有FGFR1/2驱动改变的ER+乳腺癌。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信