ABSTRACT: Multiple myeloma (MM) is a cancerous plasma cell condition that is characterized by overproduction of abnormal antibodies by plasma cells. The complete cure for the disease has not been achieved because of development of drug resistance. Bortezomib, the pioneering proteasome inhibitor, is essential in MM treatment; nevertheless, acquired resistance greatly restricts its effectiveness. To clarify the molecular mechanisms behind bortezomib resistance, we performed RNA sequencing (RNA-Seq) on RPMI-8226 MM cells that were bortezomib-sensitive and bortezomib-resistant, as well as healthy B-cells. Analysis of differential expression showed notable changes in immune signaling, proteasome activity, and metabolic pathways. Resistant MM cells showed a significant decrease in the expression of antigen presentation genes, such as HLA-DRA, HLA-DPA1, and CD74, indicating immune evasion. Meanwhile, important metabolic regulators like GLUL (Glutamine Synthetase) and MDK (Midkine) were downregulated, suggesting a transition to glycolytic metabolism. Simultaneously, the enhancement of proteasome-related processes and nucleocytoplasmic transport underscored adaptive mechanisms for preserving protein balance during proteotoxic stress. Notably, PRAME (Preferentially Expressed Antigen in Melanoma), a key oncogene often linked to therapy resistance, was significantly upregulated in resistant MM cells. Pathway analysis further indicated notable enrichment of pathways associated with neurodegenerative diseases, implying a common mechanism linking MM progression to protein misfolding disorders. Significantly, bortezomib-resistant MM cells exhibited cross-resistance to BEZ235, an inhibitor of dual PI3K/mTOR, indicating a four-fold rise in IC50 values, which suggests improved survival signaling and metabolic adaptability in resistance pathways. These results highlight the complex aspects of bortezomib resistance, fueled by metabolic reprogramming, modified immune interactions, and translational regulation. Focusing on these adaptive responses through combination treatments that include proteasome inhibitors, metabolic modulators, and autophagy inhibitors may offer innovative therapeutic approaches to tackle drug resistance in MM.
