Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition.

Autor:	Schukken KM; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands., Lin YC; Goettingen Center for Molecular Biosciences and University Medical Center, Goettingen, Germany., Bakker PL; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands., Schubert M; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands., Preuss SF; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands., Simon JE; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands., van den Bos H; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands., Storchova Z; Department of Molecular Genetics, University of Kaiserslautern, Germany., Colomé-Tatché M; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.; Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.; Technical University of Munich, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany., Bastians H; Goettingen Center for Molecular Biosciences and University Medical Center, Goettingen, Germany., Spierings DC; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands., Foijer F; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands f.foijer@umcg.nl.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2020 Jan 24; Vol. 3 (2). Date of Electronic Publication: 2020 Jan 24 (Print Publication: 2020).
DOI:	10.26508/lsa.201900499
Abstrakt:	Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. As most cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings, therefore, suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics. (© 2020 Schukken et al.)
Databáze:	MEDLINE
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