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

KeJing Zhang1, Juan Wei2, SheYu Zhang3

  • 1Zhejiang 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.

Cell Chemical Biology
|September 4, 2024
PubMed

Insights

Paclitaxel-resistant triple negative breast cancer (TNBC) shows vulnerability to protein arginine methyltransferases (PRMTs) inhibition. Targeting PRMT5 selectively induces mitosis catastrophe in resistant cells, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Paclitaxel-resistant triple negative breast cancer (TNBC) presents a significant clinical challenge.
  • Mechanisms of resistance involve the stabilization of mitotic chromatin assembly.

Purpose of the Study:

  • To identify novel therapeutic vulnerabilities in paclitaxel-resistant TNBC.
  • To investigate the role of protein arginine methyltransferases (PRMTs) in mediating resistance.

Main Methods:

  • Epigenetic chemical probe screen in TNBC cell lines.
  • Analysis of cell lines and clinical samples.
  • Genetic and pharmacologic inhibition of PRMT5 and Type I PRMTs.
  • Assessment of RNA splicing, protein expression, and cell viability.
  • Validation in a patient-derived xenograft (PDX) model.

Main Results:

  • Paclitaxel-resistant TNBC cells exhibit vulnerability to PRMT inhibition.
  • PRMT5 inhibition disrupts RNA splicing, specifically intron retention of Aurora Kinase B (AURKB).
  • This leads to decreased AURKB protein expression and selective mitosis catastrophe in resistant cells.
  • Combined inhibition of Type I PRMTs and PRMT5 synergistically suppresses tumor growth in resistant models.

Conclusions:

  • PRMT inhibition represents a promising therapeutic strategy for paclitaxel-resistant TNBC.
  • Targeting PRMT5-mediated regulation of AURKB offers a selective approach to overcome drug resistance.
  • Combined PRMT inhibition may enhance treatment efficacy in resistant TNBC.
Keywords:
AURKBPRMT5RNA splicingTNBCmitosispaclitaxel resistant

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