PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer

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 and Carlos L. Arteaga ()
Additional contact information
Chang-Ching Lin: UT Southwestern Medical Center
Tsung-Cheng Chang: UT Southwestern Medical Center
Yunguan Wang: UT Southwestern Medical Center
Lei Guo: UT Southwestern Medical Center
Yunpeng Gao: UT Southwestern Medical Center
Emmanuel Bikorimana: UT Southwestern Medical Center
Andrew Lemoff: UT Southwestern Medical Center
Yisheng V. Fang: UT Southwestern Medical Center
He Zhang: UT Southwestern Medical Center
Yanfeng Zhang: UT Southwestern Medical Center
Dan Ye: UT Southwestern Medical Center
Isabel Soria-Bretones: University of Toronto
Alberto Servetto: UT Southwestern Medical Center
Kyung-min Lee: UT Southwestern Medical Center
Xuemei Luo: UT Southwestern Medical Center
Joseph J. Otto: UT Southwestern Medical Center
Hiroaki Akamatsu: UT Southwestern Medical Center
Fabiana Napolitano: UT Southwestern Medical Center
Ram Mani: UT Southwestern Medical Center
David W. Cescon: University of Toronto
Lin Xu: UT Southwestern Medical Center
Yang Xie: UT Southwestern Medical Center
Joshua T. Mendell: UT Southwestern Medical Center
Ariella B. Hanker: UT Southwestern Medical Center
Carlos L. Arteaga: UT Southwestern Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46495-2

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