RT Journal Article
SR Electronic
T1 Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900499
DO 10.26508/lsa.201900499
VO 3
IS 2
A1 Klaske M Schukken
A1 Yu-Chih Lin
A1 Petra L Bakker
A1 Michael Schubert
A1 Stephanie F Preuss
A1 Judith E Simon
A1 Hilda van den Bos
A1 Zuzana Storchova
A1 Maria Colomé-Tatché
A1 Holger Bastians
A1 Diana CJ Spierings
A1 Floris Foijer
YR 2020
UL https://www.life-science-alliance.org/content/3/2/e201900499.abstract
AB 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.