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Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition.
Life Sci. All. 3:e201900499 (2020)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Chromosome Segregation Errors; Dna-damage Response; Mis-segregation; Colorectal-cancer; C-src; Aneuploidy; Instability; Cells; Mps1; Consequences
ISSN (print) / ISBN
2575-1077
e-ISSN
2575-1077
Journal
Life Science Alliance
Quellenangaben
Volume: 3,
Issue: 2,
Article Number: e201900499
Publisher
EMBO Press
Publishing Place
Heidelberg
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Computational Biology (ICB)