While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose‐limiting toxicities and the inevitable emergence of drug resistance limit their long‐term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy‐induced, which accounts for the majority of tumor relapses and MM‐related deaths. Non‐coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non‐coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance. While lncRNAs have recently attracted significant attention as therapeutic targets to potentially improve cancer treatment, identification of lncRNAs that are deregulated in cells resistant to PIs has not been previously addressed. We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib, carfilzomib, or ixazomib. Genome‐wide profiling identified lncRNAs that were significantly deregulated in all three PIresistant cell lines relative to the drug‐sensitive parental cell line. Strikingly, certain lncRNAs deregulated in the three PI‐resistant cell lines were also deregulated in MM plasma cells isolated from newly diagnosed patients compared to healthy plasma cells. Taken together, these preliminary studies strongly suggest that lncRNAs represent potential therapeutic targets to prevent or overcome drug resistance. More investigations are ongoing to expand these initial studies in a greater number of MM patients to better define lncRNAs signatures that contribute to PI resistance in MM.
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