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

Ke Jing Zhang; Juan Wei; She Yu Zhang; Liyan Fei; Lu Guo; Xueying Liu; Yi Shuai Ji; Wen Jun Chen; Felipe E. Ciamponi; Wei Chang Chen; Meng Xi Li; Jie Zhai; Ting Fu; Katlin B. Massirer; Yang Yu; Mathieu Lupien; Yong Wei; Cheryl H. Arrowsmith; Qin Wu; Wei Hong 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

Ke Jing Zhang
, Juan Wei
, She Yu Zhang
, Liyan Fei
, Lu Guo
, Xueying Liu
, Yi Shuai Ji
, Wen Jun Chen
, Felipe E. Ciamponi
, Wei Chang Chen
, Meng Xi Li
, Jie Zhai
, Ting Fu
, Katlin B. Massirer
, Yang Yu
, Mathieu Lupien
, Yong Wei^*
, Cheryl H. Arrowsmith^*
, Qin Wu^*
, Wei Hong Tan^*

^*Corresponding author for this work

Chinese Academy of Sciences
Department of General Surgery
Central South University
Clinical Research Center for Breast Cancer in Hunan Province
Tianjin University
Universidade Estadual de Campinas
University of Toronto
Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre
Ontario Institute for Cancer Research
Structural Genomics Consortium

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1942-1957.e6
Journal	Cell Chemical Biology
Volume	31
Issue number	11
DOIs	https://doi.org/10.1016/j.chembiol.2024.08.003
Publication status	Published - 21 Nov 2024
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

AURKB
PRMT5
RNA splicing
TNBC
mitosis
paclitaxel resistant

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10.1016/j.chembiol.2024.08.003

Cite this

Zhang, K. J., Wei, J., Zhang, S. Y., Fei, L., Guo, L., Liu, X., Ji, Y. S., Chen, W. J., Ciamponi, F. E., Chen, W. C., Li, M. X., Zhai, J., Fu, T., Massirer, K. B., Yu, Y., Lupien, M., Wei, Y., Arrowsmith, C. H., Wu, Q., & Tan, W. H. (2024). A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer. Cell Chemical Biology, 31(11), 1942-1957.e6. https://doi.org/10.1016/j.chembiol.2024.08.003

@article{9bbcc736dbd8490c9b277c5e002e908a,

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

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",

author = "Zhang, \{Ke Jing\} and Juan Wei and Zhang, \{She Yu\} and Liyan Fei and Lu Guo and Xueying Liu and Ji, \{Yi Shuai\} and Chen, \{Wen Jun\} and Ciamponi, \{Felipe E.\} and Chen, \{Wei Chang\} and Li, \{Meng Xi\} and Jie Zhai and Ting Fu and Massirer, \{Katlin B.\} and Yang Yu and Mathieu Lupien and Yong Wei and Arrowsmith, \{Cheryl H.\} and Qin Wu and Tan, \{Wei Hong\}",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Ltd",

year = "2024",

month = nov,

day = "21",

doi = "10.1016/j.chembiol.2024.08.003",

language = "English",

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Zhang, KJ, Wei, J, Zhang, SY, Fei, L, Guo, L, Liu, X, Ji, YS, Chen, WJ, Ciamponi, FE, Chen, WC, Li, MX, Zhai, J, Fu, T, Massirer, KB, Yu, Y, Lupien, M, Wei, Y, Arrowsmith, CH, Wu, Q & Tan, WH 2024, 'A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer', Cell Chemical Biology, vol. 31, no. 11, pp. 1942-1957.e6. https://doi.org/10.1016/j.chembiol.2024.08.003

TY - JOUR

T1 - A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer

AU - Zhang, Ke Jing

AU - Wei, Juan

AU - Zhang, She Yu

AU - Fei, Liyan

AU - Guo, Lu

AU - Liu, Xueying

AU - Ji, Yi Shuai

AU - Chen, Wen Jun

AU - Ciamponi, Felipe E.

AU - Chen, Wei Chang

AU - Li, Meng Xi

AU - Zhai, Jie

AU - Fu, Ting

AU - Massirer, Katlin B.

AU - Yu, Yang

AU - Lupien, Mathieu

AU - Wei, Yong

AU - Arrowsmith, Cheryl H.

AU - Wu, Qin

AU - Tan, Wei Hong

PY - 2024/11/21

Y1 - 2024/11/21

N2 - 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.

AB - 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.

KW - AURKB

KW - PRMT5

KW - RNA splicing

KW - TNBC

KW - mitosis

KW - paclitaxel resistant

UR - https://www.scopus.com/pages/publications/85207760490

U2 - 10.1016/j.chembiol.2024.08.003

DO - 10.1016/j.chembiol.2024.08.003

M3 - Article

C2 - 39232499

AN - SCOPUS:85207760490

SN - 2451-9456

VL - 31

SP - 1942-1957.e6

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 11

ER -

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

Abstract

UN SDGs

Keywords

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