Vora, S.Andrew, A.Kumar, R.P.Nazareth, D.Bonfim-Melo, A.Lim, Y.Ong, X.Y.Fernando, M.He, Y.Hooper, J.D.McMillan, N.A.Urosevic, J.Travers, J.Saeh, J.Kumar, S.Jones, M.J.Gabrielli, B.2025-03-212025-03-212024Cell Death and Disease, 2024; 15(11):810-1-810-92041-48892041-4889https://hdl.handle.net/2440/143972Aurora B kinase (AURKB) inhibitors have been trialled in a range of different tumour types but are not approved for any indication. Expression of the human papilloma virus (HPV) oncogenes and loss of retinoblastoma (RB) protein function has been reported to increase sensitivity to AURKB inhibitors but the mechanism of their contribution to sensitivity is poorly understood. Two commonly reported outcomes of AURKB inhibition are polyploidy and senescence, although their relationship is unclear. Here we have investigated the major cellular targets of the HPV E6 and E7, p53 and RB, to determine their contribution to AURKB inhibitor induced polyploidy and senescence. We demonstrate that polyploidy is a universal feature of AURKB inhibitor treatment in all cell types including normal primary cells, but the subsequent outcomes are controlled by RB and p53. We demonstrate that p53 by regulating p21 expression is required for an initial cell cycle arrest by inhibiting both CDK2 and CDK4 activity, but this arrest is only triggered after cells have undergone two failed mitosis and cytokinesis. However, cells can enter senescence in the absence of p53. RB is essential for AURKB inhibitor-induced senescence. AURKB inhibitor induces rapid hypophosphorylation of RB independent of inhibition of CDK2 or CDK4 kinases and p53. This work demonstrates that p53 activation determines the timing of senescence onset, but RB is indispensable for senescence.en© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Senescence; Targeted therapiesHumansRetinoblastoma ProteinProtein Kinase InhibitorsPhosphorylationPolyploidyTumor Suppressor Protein p53Cyclin-Dependent Kinase Inhibitor p21Cyclin-Dependent Kinase 2Cyclin-Dependent Kinase 4Cell Cycle CheckpointsAurora Kinase BCellular SenescenceJournal article10.1038/s41419-024-07204-5718016Kumar, S. [0000-0001-7126-9814]