BUB1 as a candidate non-oncogene addiction vulnerability in metastatic phaeochromocytoma/paraganglioma.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours with limited treatment options in the metastatic setting. We performed integrative transcriptomic analyses of TCGA and COMETE datasets and identified BUB1, a mitotic checkpoint kinase and prototypical non-oncogene addiction (NOA) factor, as significantly upregulated in metastatic PPGLs. We validated BUB1 overexpression in primary tumour tissues using RT-qPCR and subsequently conducted functional studies in the human phaeochromocytoma-derived hPheo1 cell line. Genetic silencing of BUB1 or its pharmacological inhibition with BAY1816032 significantly reduced cell viability, colony formation, migration, and invasion. Both interventions also decreased phosphorylation of histone H2A at threonine 120, a direct downstream target of BUB1 kinase activity. In migration and invasion assays, BUB1 inhibition impaired motility and reduced expression of the epithelial-to-mesenchymal transition (EMT) markers N-cadherin and vimentin. These findings provide the first demonstration of BUB1 overexpression in metastatic PPGL tissues. Preclinical evidence suggests that hPheo1 cells depend on BUB1 for growth, genome stability, and invasive behaviour. These findings nominate BUB1 as a candidate vulnerability and putative biomarker, warranting validation in larger, multi-institutional cohorts.