Abstract
Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases.
Highlights
Since their discovery in 1995, the aurora kinases have gained much interest as drug targets in cancer
The IC50 values of tozasertib and alisertib were determined in a panel of neuroblastoma cell lines and their drug-resistant sub-lines (Figure 1A, Table S1)
ABCB1 expression reduced cancer cell sensibility to tozasertib but not to alisertib. This is in concert with previous findings that had suggested tozasertib to be a substrate of ABCB1 [28,29]
Summary
Since their discovery in 1995, the aurora kinases have gained much interest as drug targets in cancer. There are three known homologous family members, the aurora kinases A, B, and C. They are involved in the organisation of the spindle apparatus during mitosis. MYCN amplification is a major negative prognostic factor in neuroblastoma indicating high-risk disease [3,4]. Aurora kinase A expression and amplification were shown to be negative prognostic markers in neuroblastoma and to stabilise MYCN [5,6]. Aurora kinase B was identified as drug target in neuroblastoma tumour-initiating cells with deregulated BRCA1 signalling [7]. Different aurora kinase inhibitors including the aurora kinase A inhibitors MLN8054 and alisertib (MLN8237), the aurora kinase B inhibitor AZD1152, and the pan aurora kinase inhibitor CCT137690 were demonstrated to display anti-neuroblastoma activity [5,7,8,9,10,11,12,13,14,15]
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