Whole-genome duplication increases tumor cell sensitivity to MPS1 inhibition

// Mohamed Jemaa 1 , Gwenola Manic 2 , Gwendaline Lledo 1 , Delphine Lissa 3, 4, 5, 6 , Christelle Reynes 7 , Nathalie Morin 1 , Frederic Chibon 8, 9 , Antonella Sistigu 2 , Maria Castedo 3, 4, 5, 6 , Ilio Vitale 2, 10, * , Guido Kroemer 4, 5, 11, 12, 13, * , Ariane Abrieu 1, * 1 CRBM, CNRS UMR5237, Universite de Montpellier, Montpellier, France 2 Regina Elena National Cancer Institute, Rome, Italy 3 Universite Paris-Sud/Paris XI, Le Kremlin-Bicetre, France 4 INSERM, UMRS1138, Paris, France 5 Equipe 11 Labelisee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France 6 Gustave Roussy Cancer Campus, Villejuif, France 7 EA 2415, Laboratoire de Biostatistique, d’Epidemiologie et de Recherche Clinique, Universite de Montpellier, Montpellier, France 8 Department of Biopathology, Institut Bergonie, Comprehensive Cancer Centre, Bordeaux, France 9 INSERM U916, Bordeaux, France 10 Department of Biology, University of Rome “Tor Vergata”, Rome, Italy 11 Universite Pierre et Marie Curie/Paris VI, Paris, France 12 Pole de Biologie, Hopital Europeen Georges Pompidou, AP-HP, Paris, France 13 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France * I.V., G.K., and A.A. share co-senior authorship Correspondence to: Ilio Vitale, e-mail: iliovit@gmail.com Guido Kroemer, e-mail: kroemer@orange.fr Ariane Abrieu, e-mail: ariane.abrieu@crbm.cnrs.fr Keywords: AZ 3146, mitotic spindle, polyploidy, regulated cell death, reversine Received: June 25, 2015      Accepted: November 18, 2015      Published: November 30, 2015 ABSTRACT Several lines of evidence indicate that whole-genome duplication resulting in tetraploidy facilitates carcinogenesis by providing an intermediate and metastable state more prone to generate oncogenic aneuploidy. Here, we report a novel strategy to preferentially kill tetraploid cells based on the abrogation of the spindle assembly checkpoint (SAC) via the targeting of TTK protein kinase (better known as monopolar spindle 1, MPS1). The pharmacological inhibition as well as the knockdown of MPS1 kills more efficiently tetraploid cells than their diploid counterparts. By using time-lapse videomicroscopy, we show that tetraploid cells do not survive the aborted mitosis due to SAC abrogation upon MPS1 depletion. On the contrary diploid cells are able to survive up to at least two more cell cycles upon the same treatment. This effect might reflect the enhanced difficulty of cells with whole-genome doubling to tolerate a further increase in ploidy and/or an elevated level of chromosome instability in the absence of SAC functions. We further show that MPS1-inhibited tetraploid cells promote mitotic catastrophe executed by the intrinsic pathway of apoptosis, as indicated by the loss of mitochondrial potential, the release of the pro-apoptotic cytochrome c from mitochondria, and the activation of caspases. Altogether, our results suggest that MPS1 inhibition could be used as a therapeutic strategy for targeting tetraploid cancer cells.