Abstract
The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). Seventy seven (77) cell lines displayed YM155 IC50s in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, TP53-mutant cells were not generally less sensitive to YM155 than TP53 wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.
Highlights
The inhibitor of apoptosis protein (IAP) survivin has multifaceted roles in cellular signalling
YM155 was initially tested in a panel of 86 neuroblastoma cell lines consisting of 17 parental
Cisplatin and oxaliplatin resistance were associated with a lower degree of YM155 resistance than carboplatin resistance (Figure 5C, Figure 5D, Table S1)
Summary
The inhibitor of apoptosis protein (IAP) survivin has multifaceted roles in cellular signalling. It is absent from most somatic cells but highly abundant in cancer cells and mediates cancer cell survival and proliferation. Elevated survivin levels have been associated with more aggressive and advanced cancer disease and lower survival rates. Survivin is a potential drug target in cancer entities including neuroblastoma [1,2,3,4,5,6,7,8,9,10], the most frequent solid extracranial paediatric cancer. About half of the patients are diagnosed with high-risk disease associated with overall survival rates below 50%. While many neuroblastomas respond initially well to therapy, acquired drug resistance represents a major clinical problem [11,12]
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