Molecular determinants of Bortezomib sensitivity and resistance in multiple myeloma

Bortezomib, a first-in-class proteasome inhibitor, has significantly transformed the therapeutic landscape of multiple myeloma (MM). Despite its clinical efficacy, both intrinsic and acquired resistance limit its long-term success. This review synthesizes current knowledge regarding molecular determinants of bortezomib sensitivity and resistance, with a focus on p53, Ras signaling, mTOR pathway activity, Wee1 kinase, and long non-coding RNAs (lncRNAs). p53 functions as a key mediator of bortezomib-induced apoptosis, and its loss or mutation blunts pro-apoptotic signaling. Aberrant Ras activation promotes pro-survival pathways that counteract proteotoxic stress, while mTOR signaling buffers metabolic and translational stress to support cell survival under bortezomib pressure. Wee1 kinase extends the G2/M checkpoint, granting MM cells time to repair DNA and mitigate proteotoxicity, thereby reducing sensitivity to bortezomib. In parallel, lncRNAs orchestrate multiple layers of resistance through miRNA sponging, epigenetic remodeling, metabolic rewiring, and intercellular transfer via exosomes. Each determinant contributes uniquely to cellular adaptation, stress tolerance, and survival under proteasome inhibition. Integrating these pathways reveals a complex regulatory network where apoptosis and survival signals compete, ultimately shaping drug response. We further discuss therapeutic implications, biomarker development, and emerging strategies, including RNA-based therapies, multi-omics profiling, and rational drug combinations. By expanding mechanistic understanding, this review aims to guide the design of precision strategies to overcome bortezomib resistance in MM.