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Identification of Long Non-Coding RNAs Deregulated in Multiple Myeloma Cells Resistant to Proteasome Inhibitors
Ehsan Malek1, Byung-Gyu Kim2, James J Driscoll3,4
1Division of Hematology and Oncology, University Hospitals, Case Medical Center, Seidman Cancer Center, Cleveland, OH 44106, USA. ehsan.malek@uhhospitals.org.
Abstract:
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.
Insights
Long non-coding RNAs (lncRNAs) are deregulated in multiple myeloma (MM) cells resistant to proteasome inhibitors (PIs). These lncRNAs may offer new therapeutic targets to overcome drug resistance in MM patients.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Proteasome inhibitors (PIs) are crucial for multiple myeloma (MM) treatment but face challenges from dose-limiting toxicities and acquired drug resistance.
- Drug resistance compromises disease eradication, leading to tumor relapse and MM-related mortality.
- Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), regulate critical cellular processes involved in cancer and therapeutic resistance.
Purpose of the Study:
- To identify long non-coding RNAs (lncRNAs) that are deregulated in multiple myeloma (MM) cells exhibiting acquired resistance to proteasome inhibitors (PIs).
- To explore the potential of these deregulated lncRNAs as therapeutic targets for overcoming PI resistance in MM.
Main Methods:
- Generated three MM cell lines with acquired resistance to bortezomib, carfilzomib, or ixazomib.
- Performed genome-wide profiling to identify significantly deregulated lncRNAs in PI-resistant versus drug-sensitive MM cells.
- Compared lncRNA expression profiles in resistant MM cells with those in MM patient plasma cells.
Main Results:
- Identified specific lncRNAs that were significantly deregulated across all three PI-resistant MM cell lines.
- Found that some of these deregulated lncRNAs were also altered in MM plasma cells from newly diagnosed patients compared to healthy controls.
- These findings suggest a conserved role for certain lncRNAs in PI resistance.
Conclusions:
- lncRNAs are implicated in the development of proteasome inhibitor resistance in multiple myeloma.
- lncRNAs represent promising therapeutic targets for preventing or overcoming drug resistance in MM.
- Further studies in larger patient cohorts are warranted to define lncRNA signatures associated with PI resistance.
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