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

Research output: Contribution to journalArticlepeer-review

1 Citation (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 languageEnglish
Pages (from-to)1942-1957.e6
JournalCell Chemical Biology
Volume31
Issue number11
DOIs
Publication statusPublished - 21 Nov 2024
Externally publishedYes

Keywords

  • AURKB
  • PRMT5
  • RNA splicing
  • TNBC
  • mitosis
  • paclitaxel resistant

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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