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

被引：11

作者：

Lin, Chang-Ching ^{[1
]}

Chang, Tsung-Cheng ^{[2
,3
]}

Wang, Yunguan ^{[4
,5
]}

Guo, Lei ^{[4
]}

Gao, Yunpeng ^{[6
]}

Bikorimana, Emmanuel ^{[1
]}

Lemoff, Andrew ^{[7
]}

Fang, Yisheng V. ^{[1
,6
]}

Zhang, He ^{[4
]}

Zhang, Yanfeng ^{[4
,8
]}

Ye, Dan ^{[1
]}

Soria-Bretones, Isabel ^{[9
]}

Servetto, Alberto ^{[1
,10
]}

Lee, Kyung-min ^{[1
,11
]}

Luo, Xuemei ^{[7
]}

Otto, Joseph J. ^{[7
]}

Akamatsu, Hiroaki ^{[1
,12
]}

Napolitano, Fabiana ^{[1
,10
]}

Mani, Ram ^{[6
]}

Cescon, David W. ^{[9
]}

Xu, Lin ^{[4
]}

Xie, Yang ^{[4
]}

Mendell, Joshua T. ^{[2
,3
]}

Hanker, Ariella B. ^{[1
]}

Arteaga, Carlos L. ^{[1
]}

机构：

[1] UT Southwestern Med Ctr, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[2] UT Southwestern Med Ctr, Dept Mol Biol, Dallas, TX USA

[3] UT Southwestern Med Ctr, Howard Hughes Med Inst, Dallas, TX USA

[4] Quantitat Biomed Res Ctr, UT Southwestern Med Ctr, Peter ODonnell Jr Sch Publ Hlth, Dept Populat & Data Sci, Dallas, TX USA

[5] Cincinnati Childrens Hosp Med Ctr, Div Pediat Gastroenterol Hepatol & Nutr, Cincinnati, OH USA

[6] UT Southwestern Med Ctr, Dept Pathol, Dallas, TX USA

[7] UT Southwestern Med Ctr, Dept Biochem, Dallas, TX USA

[8] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA

[9] Univ Toronto, Princess Margaret Canc Ctr, Toronto, ON, Canada

[10] Univ Naples Federico II, Dept Clin Med & Surg, Naples, Italy

[11] Hanyang Univ, Dept Life Sci, Seoul, South Korea

[12] Wakayama Med Univ, Dept Internal Med 3, Wakayama, Japan

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

关键词：

RNA-POLYMERASE-II; ARGININE METHYLATION; INTEGRATIVE ANALYSIS; DETAINED INTRONS; FUS; RECRUITMENT; BINDING; PHOSPHORYLATION; PROTEIN; CELLS;

D O I：

10.1038/s41467-024-46495-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16