The functional role of PARP14 in myeloma cell survival and drug resistance

Multiple myeloma (MM) is a hematologic malignancy characterized by the uncontrolled proliferation of plasma cells within the bone marrow, resulting in the production of abnormal monoclonal immunoglobulins. Despite significant advancements in therapeutic strategies over the past two decades, MM remains an incurable disease. Current treatment modalities for MM include immunomodulatory drugs, monoclonal antibodies, stem cell transplantation, and proteasome inhibitors, the latter of which are recognized as the most effective and widely utilized.

Proteasome inhibitors (PIs) are considered a cornerstone of myeloma treatment. By targeting the ubiquitin-proteasome pathway, PIs disrupt the degradation of misfolded proteins, which accumulate in MM cells due to their high levels of immunoglobulin production. This disruption induces proteotoxic stress, ultimately triggering apoptosis in malignant cells. However, the prolonged use of PIs often leads to the development of acquired resistance, presenting a significant clinical challenge that limits long-term therapeutic success.

The emergence of resistance to PIs in MM is a complex and multifactorial phenomenon. Recent metabolomic studies have highlighted significant alterations in lipid metabolism as a hallmark of PI-resistant MM cells. Nevertheless, the regulatory mechanisms driving these metabolic changes are not yet fully elucidated, representing a critical gap in our understanding of MM resistance.

In this study, we hypothesize that the anti-apoptotic protein PARP14 may play a pivotal role in regulating the metabolic switch observed in PI-resistant MM cells.
PARP14 is known to modulate cell survival pathways, and emerging evidence suggests its involvement in metabolic regulation in various cancers. To test this hypothesis, we employed a combination of metabolomic profiling and in-vitro and in-vivo functional analyses in PI-sensitive and PI-resistant MM cell lines and found that PARP14 plays a pivotal role in promoting fatty acid β-oxidation. Altogether our results suggest that targeting PARP14 may represent a strategic approach to overcome metabolic adaptation and drug resistance in multiple myeloma.