PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer
Abstract CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-03-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46495-2 |
| _version_ | 1797259185357848576 |
|---|---|
| author | Chang-Ching Lin Tsung-Cheng Chang Yunguan Wang Lei Guo Yunpeng Gao Emmanuel Bikorimana Andrew Lemoff Yisheng V. Fang He Zhang Yanfeng Zhang Dan Ye Isabel Soria-Bretones Alberto Servetto Kyung-min Lee Xuemei Luo Joseph J. Otto Hiroaki Akamatsu Fabiana Napolitano Ram Mani David W. Cescon Lin Xu Yang Xie Joshua T. Mendell Ariella B. Hanker Carlos L. Arteaga |
| author_facet | Chang-Ching Lin Tsung-Cheng Chang Yunguan Wang Lei Guo Yunpeng Gao Emmanuel Bikorimana Andrew Lemoff Yisheng V. Fang He Zhang Yanfeng Zhang Dan Ye Isabel Soria-Bretones Alberto Servetto Kyung-min Lee Xuemei Luo Joseph J. Otto Hiroaki Akamatsu Fabiana Napolitano Ram Mani David W. Cescon Lin Xu Yang Xie Joshua T. Mendell Ariella B. Hanker Carlos L. Arteaga |
| author_sort | Chang-Ching Lin |
| collection | DOAJ |
| description | Abstract CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identify protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout breast cancer cells. Inhibition of PRMT5 blocks the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RB1-knockout cells. Proteomics analysis uncovers fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 results in dissociation of FUS from RNA polymerase II, leading to hyperphosphorylation of serine 2 in RNA polymerase II, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibits growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight dual ER and PRMT5 blockade as a potential therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer. |
| first_indexed | 2024-04-24T23:05:24Z |
| format | Article |
| id | doaj.art-e4a5c7d11ac44ac3ba09402a88d94d20 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T23:05:24Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e4a5c7d11ac44ac3ba09402a88d94d202024-03-17T12:31:21ZengNature PortfolioNature Communications2041-17232024-03-0115111610.1038/s41467-024-46495-2PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancerChang-Ching Lin0Tsung-Cheng Chang1Yunguan Wang2Lei Guo3Yunpeng Gao4Emmanuel Bikorimana5Andrew Lemoff6Yisheng V. Fang7He Zhang8Yanfeng Zhang9Dan Ye10Isabel Soria-Bretones11Alberto Servetto12Kyung-min Lee13Xuemei Luo14Joseph J. Otto15Hiroaki Akamatsu16Fabiana Napolitano17Ram Mani18David W. Cescon19Lin Xu20Yang Xie21Joshua T. Mendell22Ariella B. Hanker23Carlos L. Arteaga24Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical CenterDepartment of Molecular Biology, UT Southwestern Medical CenterQuantitative Biomedical Research Center, Department of Population & Data Sciences, Peter O’Donnell Jr. School of Public Health, UT Southwestern Medical CenterQuantitative Biomedical Research Center, Department of Population & Data Sciences, Peter O’Donnell Jr. School of Public Health, UT Southwestern Medical CenterDepartment of Pathology, UT Southwestern Medical CenterHarold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical CenterDepartment of Biochemistry, UT Southwestern Medical CenterHarold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical CenterQuantitative Biomedical Research Center, Department of Population & Data Sciences, Peter O’Donnell Jr. School of Public Health, UT Southwestern Medical CenterQuantitative Biomedical Research Center, Department of Population & Data Sciences, Peter O’Donnell Jr. School of Public Health, UT Southwestern Medical CenterHarold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical CenterPrincess Margaret Cancer Centre, University of TorontoHarold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical CenterHarold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical CenterDepartment of Biochemistry, UT Southwestern Medical CenterDepartment of Biochemistry, UT Southwestern Medical CenterHarold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical CenterHarold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical CenterDepartment of Pathology, UT Southwestern Medical CenterPrincess Margaret Cancer Centre, University of TorontoQuantitative Biomedical Research Center, Department of Population & Data Sciences, Peter O’Donnell Jr. School of Public Health, UT Southwestern Medical CenterQuantitative Biomedical Research Center, Department of Population & Data Sciences, Peter O’Donnell Jr. School of Public Health, UT Southwestern Medical CenterDepartment of Molecular Biology, UT Southwestern Medical CenterHarold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical CenterHarold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical CenterAbstract CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identify protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout breast cancer cells. Inhibition of PRMT5 blocks the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RB1-knockout cells. Proteomics analysis uncovers fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 results in dissociation of FUS from RNA polymerase II, leading to hyperphosphorylation of serine 2 in RNA polymerase II, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibits growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight dual ER and PRMT5 blockade as a potential therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.https://doi.org/10.1038/s41467-024-46495-2 |
| spellingShingle | Chang-Ching Lin Tsung-Cheng Chang Yunguan Wang Lei Guo Yunpeng Gao Emmanuel Bikorimana Andrew Lemoff Yisheng V. Fang He Zhang Yanfeng Zhang Dan Ye Isabel Soria-Bretones Alberto Servetto Kyung-min Lee Xuemei Luo Joseph J. Otto Hiroaki Akamatsu Fabiana Napolitano Ram Mani David W. Cescon Lin Xu Yang Xie Joshua T. Mendell Ariella B. Hanker Carlos L. Arteaga PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer Nature Communications |
| title | PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer |
| title_full | PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer |
| title_fullStr | PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer |
| title_full_unstemmed | PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer |
| title_short | PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer |
| title_sort | prmt5 is an actionable therapeutic target in cdk4 6 inhibitor resistant er rb deficient breast cancer |
| url | https://doi.org/10.1038/s41467-024-46495-2 |
| work_keys_str_mv | AT changchinglin prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT tsungchengchang prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT yunguanwang prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT leiguo prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT yunpenggao prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT emmanuelbikorimana prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT andrewlemoff prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT yishengvfang prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT hezhang prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT yanfengzhang prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT danye prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT isabelsoriabretones prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT albertoservetto prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT kyungminlee prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT xuemeiluo prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT josephjotto prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT hiroakiakamatsu prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT fabiananapolitano prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT rammani prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT davidwcescon prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT linxu prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT yangxie prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT joshuatmendell prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT ariellabhanker prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer AT carloslarteaga prmt5isanactionabletherapeutictargetincdk46inhibitorresistanterrbdeficientbreastcancer |