BUB1 in cancer genetics and oncogenomics: from chromosomal instability to therapeutic vulnerabilities.

BUB1 is a serine/threonine kinase and a core component of the spindle assembly checkpoint that safeguards faithful chromosome segregation during mitosis. Accumulating studies have shown that BUB1 is aberrantly expressed across multiple malignancies and contributes to tumor progression through both canonical mitotic functions and noncanonical extramitotic activities. In this review, we summarize the genetic and functional roles of BUB1 in cancer, with a focus on its involvement in chromosomal instability, aneuploidy, therapeutic resistance, and immune evasion. We discuss how BUB1 dysregulation is associated with adverse clinicopathological features and poor prognosis in several tumor types, while also highlighting context-dependent heterogeneity across cancers. Mechanistically, BUB1 contributes to malignant phenotypes by modulating mitotic checkpoint signaling, DNA damage responses, epithelial-mesenchymal transition, ferroptosis sensitivity, cancer stemness, and innate immune signaling. We further review current preclinical evidence supporting BUB1 as a therapeutic target, including the antitumor activity of small-molecule inhibitors and their synergistic potential in combination with radiotherapy, platinum agents, taxanes, and PARP inhibitors. Finally, we outline key unresolved questions, including the critical and still unresolved distinction between kinase-dependent and scaffold-dependent functions-which directly impacts inhibitor design and druggability-toxicity concerns in normal proliferating tissues, and the need for biomarker-guided patient stratification. Collectively, BUB1 represents a preclinically supported but still incompletely validated target in cancer genetics and oncogenomics.