Unraveling bortezomib resistance in multiple myeloma: insights from RNA-Seq and PI3K/mTOR pathway analysis

Multiple Myeloma (MM), characterized by abnormal plasma cell proliferation, lacks curative treatment due to drug resistance, notably against Bortezomib, a critical proteasome inhibitor. To elucidate resistance mechanisms, we conducted RNA sequencing on Bortezomib-sensitive and resistant RPMI-8226 MM cells, comparing them to healthy B-cells. Differential expression analysis highlighted significant alterations in immune signaling, proteasome function, and metabolism. Resistant MM cells exhibited decreased antigen-presentation genes (HLA-DRA, HLA-DPA1, CD74), indicating immune evasion. Downregulation of metabolic regulators like GLUL and MDK suggested a glycolytic metabolic shift, whereas enhanced proteasome activities and nucleocytoplasmic transport represented adaptive strategies against proteotoxic stress. Importantly, resistant cells showed notable upregulation of PRAME and FAF1 genes, as oncogenes and apoptosis-related genes linked to therapy resistance.  Pathway analysis revealed enrichment in neurodegenerative disease-related pathways, suggesting common protein misfolding mechanisms in MM progression. Additionally, resistant cells displayed cross-resistance to the dual phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitor BEZ235, with a four-fold increase in IC₅₀ values, reflecting enhanced survival signaling and metabolic flexibility. These findings underscore the multifaceted nature of Bortezomib resistance, driven by metabolic reprogramming, immune modulation, and translational regulation. Targeting these adaptive pathways through combination therapies involving proteasome inhibitors, metabolic modulators, and autophagy inhibitors may present novel strategies to overcome drug resistance in MM.

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