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

Paclitaxel -resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. 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. 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. To explore the role of PRMT5 in paclitaxel-resistant triple-negative breast cancer (TNBC), we established paclitaxel-resistant cell lines derived from TNBC cell lines (MDA-MB-436, Hs578T). We then performed RNA-seq sequencing on the paclitaxel-resistant cells treated with a PRMT5 inhibitor (LLY283 or GSK591, 1μM). Additionally, to validate the clinical significance of PRMT5 in overcoming paclitaxel resistance, we conducted RNA-seq sequencing on patient-derived xenograft (PDX) models generated from paclitaxel-resistant TNBC patients treated with a PRMT5 inhibitor (LLY283, 40mg/kg).