In a study published in Cell Chemical Biology, a research team led by Prof. TAN Weihong and Prof. WU Qin from the Hangzhou Institute of Medicine of the Chinese Academy of Sciences has identified protein arginine methyltransferases (PRMTs), crucial regulators of RNA splicing and chromatin stability, as a new therapeutic target for overcoming paclitaxel resistance in triple-negative breast cancer (TNBC).

Based on previous research by Prof. WU's team (Nature Chemical Biology), which uncovered a novel mechanism of targeting RNA splicing to regulate tumour-intrinsic immunity, this study further reveals a new mechanism of disrupting RNA splicing regulation in paclitaxel resistance through PRMT inhibitors.

These findings have offered new therapeutic targets for the treatment of triple-negative breast cancer (TNBC).

TNBC is notoriously difficult to treat due to its lack of oestrogen and progesterone receptors as well as the absence of HER2 overexpression.

While paclitaxel is initially effective for many patients, resistance to the drug commonly develops within 5–7 months, leading to disease progression and limited treatment options. 

This study highlights the role of epigenetic modifications in promoting paclitaxel resistance, particularly through chromatin-mediated repression of transposable elements, which silences the viral mimicry response and supports tumour survival.

Researchers generated three distinct paclitaxel-resistant TNBC cell lines and, through extensive screening, identified a heightened sensitivity of these resistant cells to PRMT5 inhibitors. 

Using a combination of cellular biology and bioinformatics techniques, they discovered that PRMT inhibition impairs chromosomal stability and disrupts RNA splicing, notably affecting the mitotic checkpoint regulator AURKB.

By inducing intron retention within the AURKB gene, PRMT inhibitors prevent the proper translation of this critical protein, thereby reducing chromosomal stability and triggering cell apoptosis.

The therapeutic potential of PRMT inhibition was validated in both patient-derived xenograft (PDX) models and clinical samples.

In addition, it was demonstrated that combining PRMT5 inhibitors with Type I PRMT inhibitors synergistically suppresses the growth of paclitaxel-resistant TNBC cells, providing a promising new strategy for combating drug resistance.

This study identifies PRMTs as pivotal therapeutic targets in paclitaxel-resistant TNBC and uncovers novel mechanisms by which PRMT inhibition induces cancer cell death through RNA splicing alterations and chromosomal instability.

It offers a promising avenue for developing effective treatments to overcome paclitaxel resistance and improve the survival of TNBC patients.

Source: Chinese Academy of Sciences Headquarters