A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer

KeJing Zhang; Juan Wei; SheYu Zhang; Liyan Fei; Lu Guo; Xueying Liu; YiShuai Ji; WenJun Chen; Felipe E Ciamponi; WeiChang Chen; MengXi Li; Jie Zhai; Ting Fu; Katlin B Massirer; Yang Yu; Mathieu Lupien; Yong Wei; Cheryl H Arrowsmith; Qin Wu; WeiHong Tan

doi:10.1016/j.chembiol.2024.08.003

A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer

Cell Chem Biol. 2024 Nov 21;31(11):1942-1957.e6. doi: 10.1016/j.chembiol.2024.08.003. Epub 2024 Sep 3.

Authors

KeJing Zhang¹, Juan Wei², SheYu Zhang³, Liyan Fei², Lu Guo², Xueying Liu², YiShuai Ji³, WenJun Chen², Felipe E Ciamponi⁴, WeiChang Chen², MengXi Li⁵, Jie Zhai², Ting Fu², Katlin B Massirer⁴, Yang Yu², Mathieu Lupien⁶, Yong Wei⁷, Cheryl H Arrowsmith⁸, Qin Wu⁹, WeiHong Tan¹⁰

Affiliations

¹ Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410083, China; Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan 410000, China.
² Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
³ Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
⁴ Molecular Biology and Genetic Engineering Center (CBMEG), Medicinal Chemistry Center (CQMED), Structural Genomics Consortium (SGC-UNICAMP), University of Campinas-UNICAMP, Campinas 13083-872, Brazil.
⁵ Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410083, China; Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan 410000, China.
⁶ Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A1, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C4, Canada; Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
⁷ Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China. Electronic address: weiyong@ibmc.ac.cn.
⁸ Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5S 1A1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A1, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C4, Canada. Electronic address: cheryl.arrowsmith@uhnresearch.ca.
⁹ Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China. Electronic address: wuqin@ibmc.ac.cn.
¹⁰ Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China. Electronic address: tan@hnu.edu.cn.

PMID: 39232499
DOI: 10.1016/j.chembiol.2024.08.003

Abstract

Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.

Keywords: AURKB; PRMT5; RNA splicing; TNBC; mitosis; paclitaxel resistant.

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Aurora Kinase B / antagonists & inhibitors
Aurora Kinase B / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm* / drug effects
Drug Screening Assays, Antitumor
Female
Humans
Mice
Paclitaxel* / pharmacology
Protein-Arginine N-Methyltransferases* / antagonists & inhibitors
Protein-Arginine N-Methyltransferases* / genetics
Protein-Arginine N-Methyltransferases* / metabolism
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology

Substances

Paclitaxel
Protein-Arginine N-Methyltransferases
PRMT5 protein, human
Antineoplastic Agents
Aurora Kinase B
AURKB protein, human