抑制FGF受体可阻断CCDC6-RET重排甲状腺癌对RET抑制的适应性抵抗。

The Tokushima journal of experimental medicine Pub Date : 2022-06-06 Epub Date: 2022-05-05 DOI:10.1084/jem.20210390
Renuka Raman, Jacques A Villefranc, Timothy M Ullmann, Jessica Thiesmeyer, Viviana Anelli, Jun Yao, James R Hurley, Chantal Pauli, Rohan Bareja, Kenneth Wha Eng, Princesca Dorsaint, David C Wilkes, Shaham Beg, Sarah Kudman, Reid Shaw, Michael Churchill, Adnan Ahmed, Laurel Keefer, Ian Misner, Donna Nichol, Naveen Gumpeni, Theresa Scognamiglio, Mark A Rubin, Carla Grandori, James Patrick Solomon, Wei Song, Juan Miguel Mosquera, Noah Dephoure, Andrea Sboner, Olivier Elemento, Yariv Houvras
{"title":"抑制FGF受体可阻断CCDC6-RET重排甲状腺癌对RET抑制的适应性抵抗。","authors":"Renuka Raman, Jacques A Villefranc, Timothy M Ullmann, Jessica Thiesmeyer, Viviana Anelli, Jun Yao, James R Hurley, Chantal Pauli, Rohan Bareja, Kenneth Wha Eng, Princesca Dorsaint, David C Wilkes, Shaham Beg, Sarah Kudman, Reid Shaw, Michael Churchill, Adnan Ahmed, Laurel Keefer, Ian Misner, Donna Nichol, Naveen Gumpeni, Theresa Scognamiglio, Mark A Rubin, Carla Grandori, James Patrick Solomon, Wei Song, Juan Miguel Mosquera, Noah Dephoure, Andrea Sboner, Olivier Elemento, Yariv Houvras","doi":"10.1084/jem.20210390","DOIUrl":null,"url":null,"abstract":"<p><p>Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082625/pdf/","citationCount":"0","resultStr":"{\"title\":\"Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.\",\"authors\":\"Renuka Raman, Jacques A Villefranc, Timothy M Ullmann, Jessica Thiesmeyer, Viviana Anelli, Jun Yao, James R Hurley, Chantal Pauli, Rohan Bareja, Kenneth Wha Eng, Princesca Dorsaint, David C Wilkes, Shaham Beg, Sarah Kudman, Reid Shaw, Michael Churchill, Adnan Ahmed, Laurel Keefer, Ian Misner, Donna Nichol, Naveen Gumpeni, Theresa Scognamiglio, Mark A Rubin, Carla Grandori, James Patrick Solomon, Wei Song, Juan Miguel Mosquera, Noah Dephoure, Andrea Sboner, Olivier Elemento, Yariv Houvras\",\"doi\":\"10.1084/jem.20210390\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer.</p>\",\"PeriodicalId\":23015,\"journal\":{\"name\":\"The Tokushima journal of experimental medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-06-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082625/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Tokushima journal of experimental medicine\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1084/jem.20210390\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/5/5 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Tokushima journal of experimental medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1084/jem.20210390","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/5/5 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

RET 基因的改变会导致 ERK 和 AKT 信号的激活,并与遗传性和散发性甲状腺癌和肺癌有关。最近,高选择性 RET 抑制剂在治疗携带 RET 基因重排或激活突变的不同肿瘤类型患者中显示出疗效,并已进入临床应用。为了了解RET抑制剂治疗后产生的耐药机制,我们对一名RET基因重排甲状腺癌患者进行了全面的分子和基因组分析。通过药物筛选和蛋白质组及生化分析相结合的方法,我们发现了一种对 RET 抑制剂的适应性抗药性,这种抗药性会在药物暴露后数小时内重新激活 ERK 信号。我们发现,表皮生长因子受体(FGFR)信号的激活是对RET抑制剂产生适应性抗性的一种机制,它能激活ERK信号。在CCDC6-RET重组甲状腺癌的细胞模型和动物模型中,联合抑制FGFR和RET可以防止对RET抑制剂产生适应性抗药性、降低细胞活力并减少肿瘤生长。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
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