Expression of the checkpoint kinase BUB1 is a predictor of response to cancer therapies

Abstract

The identification of clinically-relevant biomarkers is of upmost importance for the management of cancer, from diagnosis to treatment choices. We performed a pan-cancer analysis of the mitotic checkpoint budding uninhibited by benzimidazole 1 gene BUB1, in the attempt to ascertain its diagnostic and prognostic values, specifically in the context of drug response. BUB1 was found to be overexpressed in the majority of cancers, and particularly elevated in clinically aggressive molecular subtypes. Its expression was correlated with clinico-phenotypic features, notably tumour staging, size, invasion, hypoxia, and stemness. In terms of prognostic value, the expression of BUB1 bore differential clinical outcomes depending on the treatment administered in TCGA cancer cohorts, suggesting sensitivity or resistance, depending on the expression levels. We also integrated in vitro drug sensitivity data from public projects based on correlation between drug efficacy and BUB1 expression to produce a list of candidate compounds with differential responses according to BUB1 levels. Gene Ontology enrichment analyses revealed that BUB1 overexpression in cancer is associated with biological processes related to mitosis and chromosome segregation machinery, reflecting the mechanisms of action of drugs with a differential effect based on BUB1 expression.

BUB1 Inhibition Sensitizes TNBC Cell Lines to Chemotherapy and Radiotherapy

“…Molecularly targeted agents can enhance chemoradiation sensitivity [ 13 ]. Given BUB1’s strong correlation to aggressiveness and different classes of drugs [ 23 ] and our observation that BUB1 inhibition sensitizes TNBC to radiation and lung cancers to chemoradiation [ 27 , 31 ], we rationalized that combining BUB1 inhibitors would provide strong chemoradiation sensitization in TNBC. Although the effectiveness of the BUB1 inhibitor BAY1816032 was evaluated with PARPi, cisplatin, and paclitaxel in a prior study [ 30 ], the combination with cisplatin resulted in antagonistic effects, and BUB1’s potential role in improving the efficacy of chemoradiation in TNBC was not assessed.…”

“…BUB1 is overexpressed in most solid cancers. BUB1 transcripts are significantly higher in breast cancer cell lines and in high-grade primary breast cancer tissues compared to normal mammary epithelial cells or in normal breast tissues [ 22 , 23 ]. Moreover, high BUB1 expression (transcript) correlates with extremely poor outcomes in breast cancer [ 24 , 25 ].…”

“…Therefore, the main objective of this study was to ascertain if BUB1 inhibition improved the effectiveness of chemotherapy and chemoradiation in TNBC cell lines. Given BUB1’s strong correlation to aggressiveness and different classes of drugs [ 23 ], and our observation that BUB1 inhibition sensitizes TNBC to radiation and lung cancers to chemoradiation [ 31 , 32 ], we rationalized that combining BUB1 inhibitors with different classes of drugs (platinum, PARPi, microtubule depolarization inhibitors) would provide strong chemoradiation sensitization in TNBC.…”