Inhibition of Aurora B kinase activity triggers senescence that can be bypassed by blocking p53 and RB function, promoting replication stress

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Andrews, Ariel
Kumar, Ramyashree Prasanna
Nazareth, Deborah
Ehmann, Anna
Hooper, John
McMillan, Nigel
Gabrielli, Brian
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Boston, MA, USA


Aurora B kinase has a major role in regulating progression through mitosis and partitioning the replicated genome at exit from mitosis and cytokinesis. We have previously reported that Aurora A and B inhibitors selectively targeted HPV-driven tumours, and that the HPV E7 oncogene is a major determinant of this selectivity. Another group has shown that sensitivity to Aurora B inhibitor AZD2811 is dependent on loss of the retinoblastoma protein (RB). Here we have investigated the outcomes of inhibition of Aurora B using selective and pan Aurora inhibitors. We show that inhibition of Aurora A and B promotes more cell death, although a subset of cells are protected from the cytotoxic effects as a consequence of Aurora A inhibition slowing the cell cycle. Aurora B inhibition promotes senescence, although this requires at least two cycles of failed cytokinesis in all cell types, including primary fibroblasts. Loss of RB function either by HPV E7 or CDK4 R24C mutant over-expression, and loss of p53 function have somewhat different effects on the outcomes of Aurora B inhibition, although both reduced the proportion of cells that entered senescence. Loss of either also promoted replication stress which was not observed in RB and p53 proficient cells, the level of replication stress was not enhanced by Aurora A co-inhibition. Selective Aurora B inhibitor was also less toxic to proliferating PBMC derive CD3+ T cells than the pan Aurora inhibitor. Together these data indicate that short term treatment with Aurora B selective inhibitor is sufficient to promote cell cycle arrest and senescence in RB and p53 proficient cells, although proliferating T cells appear to tolerate this. RB and p53 pathway defective cells are less sensitive to this senescence trigger, but undergo replication stress.

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Andrews, A; Kumar, RP; Nazareth, D; Ehmann, A; Hooper, J; McMillan, N; Gabrielli, B, Inhibition of Aurora B kinase activity triggers senescence that can be bypassed by blocking p53 and RB function, promoting replication stress, Molecular Cancer Therapeutics, 2019, 18 (12)