1. PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer
- Author
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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
- Subjects
Science - 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.
- Published
- 2024
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