Renyan Liu,Xin Wang,Timothy B Branigan,Daryl Griffin,Caoibhne McSweeney,Jie Hao,Constantia Pantelidou,Zachary T Herbert,Heta Jadhav,Geoffrey I Shapiro
{"title":"BET溴域抑制通过诱导miR-34a-5p逆转雌激素受体阳性乳腺癌中CDK4/6抑制剂的耐药性。","authors":"Renyan Liu,Xin Wang,Timothy B Branigan,Daryl Griffin,Caoibhne McSweeney,Jie Hao,Constantia Pantelidou,Zachary T Herbert,Heta Jadhav,Geoffrey I Shapiro","doi":"10.1158/1078-0432.ccr-25-1406","DOIUrl":null,"url":null,"abstract":"PURPOSE\r\nCDK6 overexpression is one critical determinant of acquired CDK4/6 inhibitor resistance. Because BRD4 is recruited to the CDK6 promoter, we investigated the potential of bromodomain and extra-terminal domain (BET) inhibition to reverse CDK4/6 inhibitor resistance.\r\n\r\nEXPERIMENTAL DESIGN\r\nCell viability and survival assays and cell line xenografts were utilized to evaluate BET inhibition in palbociclib-resistant breast cancer cells. Vehicle- and BET inhibitor-treated cells were subjected to RNA sequencing. CDK6 promoter activity was assessed with luciferase assays, and the miRPathDB V2.0 database was used to identify potential miRNAs mediating the effects of BET inhibition. Experiments were conducted to determine whether continued palbociclib treatment is essential for BET inhibitor efficacy and to explore associated mechanisms.\r\n\r\nRESULTS\r\nIn CDK4/6 inhibitor-resistant models overexpressing CDK6, a cell cycle gene signature was differentially downregulated following BET inhibition. The BET inhibitors JQ1 and ZEN-3694 reduced the expression of CDK6 and cyclin D1, reinstated CDK4/6 inhibitor-induced cell cycle arrest, and triggered apoptosis in vitro, as well as tumor regression in vivo. Mechanistically, BET inhibition downregulated CDK6 expression through the induction of miR-34a-5p, rather than by directly repressing the CDK6 promoter. Introduction of a miR-34a-5p inhibitor abrogated BET inhibitor-mediated molecular changes, whereas a miR-34a-5p mimic replicated the effects of BET inhibition. Lastly, resistant cells exhibited downregulation of BCL-2 in the presence of continued palbociclib, associated with reduced ER⍺ expression, facilitating sensitivity to BET inhibition.\r\n\r\nCONCLUSIONS\r\nOur findings highlight BET inhibition or application of miR-34a-5p mimics as promising strategies to reverse CDK4/6 inhibitor resistance in a subset of ER+ breast cancers.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"20 1","pages":""},"PeriodicalIF":10.2000,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"BET bromodomain inhibition reverses CDK4/6 inhibitor resistance in estrogen receptor-positive breast cancer via induction of miR-34a-5p.\",\"authors\":\"Renyan Liu,Xin Wang,Timothy B Branigan,Daryl Griffin,Caoibhne McSweeney,Jie Hao,Constantia Pantelidou,Zachary T Herbert,Heta Jadhav,Geoffrey I Shapiro\",\"doi\":\"10.1158/1078-0432.ccr-25-1406\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"PURPOSE\\r\\nCDK6 overexpression is one critical determinant of acquired CDK4/6 inhibitor resistance. Because BRD4 is recruited to the CDK6 promoter, we investigated the potential of bromodomain and extra-terminal domain (BET) inhibition to reverse CDK4/6 inhibitor resistance.\\r\\n\\r\\nEXPERIMENTAL DESIGN\\r\\nCell viability and survival assays and cell line xenografts were utilized to evaluate BET inhibition in palbociclib-resistant breast cancer cells. Vehicle- and BET inhibitor-treated cells were subjected to RNA sequencing. CDK6 promoter activity was assessed with luciferase assays, and the miRPathDB V2.0 database was used to identify potential miRNAs mediating the effects of BET inhibition. Experiments were conducted to determine whether continued palbociclib treatment is essential for BET inhibitor efficacy and to explore associated mechanisms.\\r\\n\\r\\nRESULTS\\r\\nIn CDK4/6 inhibitor-resistant models overexpressing CDK6, a cell cycle gene signature was differentially downregulated following BET inhibition. The BET inhibitors JQ1 and ZEN-3694 reduced the expression of CDK6 and cyclin D1, reinstated CDK4/6 inhibitor-induced cell cycle arrest, and triggered apoptosis in vitro, as well as tumor regression in vivo. Mechanistically, BET inhibition downregulated CDK6 expression through the induction of miR-34a-5p, rather than by directly repressing the CDK6 promoter. Introduction of a miR-34a-5p inhibitor abrogated BET inhibitor-mediated molecular changes, whereas a miR-34a-5p mimic replicated the effects of BET inhibition. Lastly, resistant cells exhibited downregulation of BCL-2 in the presence of continued palbociclib, associated with reduced ER⍺ expression, facilitating sensitivity to BET inhibition.\\r\\n\\r\\nCONCLUSIONS\\r\\nOur findings highlight BET inhibition or application of miR-34a-5p mimics as promising strategies to reverse CDK4/6 inhibitor resistance in a subset of ER+ breast cancers.\",\"PeriodicalId\":10279,\"journal\":{\"name\":\"Clinical Cancer Research\",\"volume\":\"20 1\",\"pages\":\"\"},\"PeriodicalIF\":10.2000,\"publicationDate\":\"2025-10-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/1078-0432.ccr-25-1406\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1078-0432.ccr-25-1406","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
BET bromodomain inhibition reverses CDK4/6 inhibitor resistance in estrogen receptor-positive breast cancer via induction of miR-34a-5p.
PURPOSE
CDK6 overexpression is one critical determinant of acquired CDK4/6 inhibitor resistance. Because BRD4 is recruited to the CDK6 promoter, we investigated the potential of bromodomain and extra-terminal domain (BET) inhibition to reverse CDK4/6 inhibitor resistance.
EXPERIMENTAL DESIGN
Cell viability and survival assays and cell line xenografts were utilized to evaluate BET inhibition in palbociclib-resistant breast cancer cells. Vehicle- and BET inhibitor-treated cells were subjected to RNA sequencing. CDK6 promoter activity was assessed with luciferase assays, and the miRPathDB V2.0 database was used to identify potential miRNAs mediating the effects of BET inhibition. Experiments were conducted to determine whether continued palbociclib treatment is essential for BET inhibitor efficacy and to explore associated mechanisms.
RESULTS
In CDK4/6 inhibitor-resistant models overexpressing CDK6, a cell cycle gene signature was differentially downregulated following BET inhibition. The BET inhibitors JQ1 and ZEN-3694 reduced the expression of CDK6 and cyclin D1, reinstated CDK4/6 inhibitor-induced cell cycle arrest, and triggered apoptosis in vitro, as well as tumor regression in vivo. Mechanistically, BET inhibition downregulated CDK6 expression through the induction of miR-34a-5p, rather than by directly repressing the CDK6 promoter. Introduction of a miR-34a-5p inhibitor abrogated BET inhibitor-mediated molecular changes, whereas a miR-34a-5p mimic replicated the effects of BET inhibition. Lastly, resistant cells exhibited downregulation of BCL-2 in the presence of continued palbociclib, associated with reduced ER⍺ expression, facilitating sensitivity to BET inhibition.
CONCLUSIONS
Our findings highlight BET inhibition or application of miR-34a-5p mimics as promising strategies to reverse CDK4/6 inhibitor resistance in a subset of ER+ breast cancers.
期刊介绍:
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.