Journal Article

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

Chang, Tsung-Cheng, Lee, Kyung-min, Mendell, Joshua T., Mani, Ram, Xu, Lin, Cescon, David W., Ye, Dan, Hanker, Ariella B., Wang, Yunguan, Soria-Bretones, Isabel, Arteaga, Carlos L., Lin, Chang-Ching, Otto, Joseph J., Luo, Xuemei, Zhang, He, Guo, Lei, Napolitano, Fabiana, Fang, Yisheng V., Akamatsu, Hiroaki, Xie, Yang, Zhang, Yanfeng, Gao, Yunpeng, Bikorimana, Emmanuel, Servetto, Alberto, Lemoff, Andrew

2024

Overview

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. CDK4/6 inhibitors have improved outcomes for patients with ER+ breast cancer, however, those with loss of RB1 function often fail to respond. Here, the authors identify a vulnerability of ER + /RB1- breast cancer on PRMT5 and via dual blockade of ER and PRMT5 therapeutically target this in patient-derived xenograft models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 38 / 45 / 49 / 631/67/1059/2326 / 631/67/1059/602 / 631/67/1347 / Breast cancer / Cell cycle / CRISPR / Cyclin-dependent kinase 4 / DNA biosynthesis / DNA-directed RNA polymerase / Down-regulation / Drug resistance / Estrogen receptors / Estrogens / Fulvestrant / FUS protein / Genomes / Humanities and Social Sciences / Inhibitors / multidisciplinary / Patients / Phosphorylation / Protein arginine methyltransferase / Proteins / Proteomics / Ribonucleic acid / RNA / RNA polymerase / RNA polymerase II / Sarcoma / Science / Science (multidisciplinary) / Therapeutic targets / Xenografts / Xenotransplantation