Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers.

Epigenetic changes drive gene expression alterations, contributing to oncogenesis and drug resistance. Lysosomes play a key role in cell signaling and sequestering toxins, including chemotherapeutic agents, which are then expelled through lysosomal exocytosis-a process linked to drug resistance. However, the epigenetic regulation of lysosomal exocytosis is poorly understood. We hypothesize that epigenetic modifier drugs (epidrugs) inhibiting this exocytosis could serve as potential cancer therapeutics. To explore this, we screened more than 150 epidrugs targeting various epigenetic proteins for their combined cytotoxic effects with cisplatin, their impact on lysosomal exocytosis, and lysosomal biogenesis. Two type I PRMT inhibitors, MS023 and GSK3368715, showed synergy with cisplatin, reduced cell viability, and inhibited lysosomal exocytosis without altering lysosomal biogenesis gene expression. RNA-seq analysis revealed differentially expressed genes involved in vesicular trafficking and lysosome dynamics, suggesting novel regulatory mechanisms. These inhibitors also synergized with other lysosome-sequestered drugs, indicating a broader application in overcoming drug resistance. Analysis of patient data further linked lower type I PRMT levels to better responses, highlighting their potential as combination therapy candidates to enhance chemotherapy efficacy and improve cancer survival rates.