Aurora B inhibition promotes a hyper-polyploid state and continued endomitotic cycles in RB and p53 defective cells

Abstract

Aurora B kinase (AURKB) inhibitors have been trialed in a range of different tumour types but are not approved for any indication. Expression of the 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 is required for an initial cell cycle arrest, but this arrest is only triggered after cells have undergone two failed mitosis and cytokinesis, but cells can enter senescence in the absence of p53. RB is essential AURKB inhibitor-induced senescence, and AURKB inhibitor induces hypophosphorylation of RB independent of inhibition of CDK2 or CDK4 kinases and p53. Hypophosphorylation is driven by enhanced dephosphorylation of RB. This work defines how p53 and RB interact to promote senescence by downregulating a suite of cell cycle regulators that are targets for E2F and DREAM repression.