TY - JOUR
T1 - Stable aneuploid tumors cells are more sensitive to TTK inhibition than chromosomally unstable cell lines
AU - Libouban, Marion A.A.
AU - de Roos, Jeroen A.D.M.
AU - Uitdehaag, Joost C.M.
AU - Willemsen-Seegers, Nicole
AU - Mainardi, Sara
AU - Dylus, Jelle
AU - Man, Jos de
AU - Tops, Bastiaan
AU - Meijerink, Jules P.P.
AU - Storchová, Zuzana
AU - Buijsman, Rogier C.
AU - Medema, René H.
AU - Zaman, Guido J.R.
N1 - Publisher Copyright:
© Libouban et al.
PY - 2017
Y1 - 2017
N2 - Inhibition of the spindle assembly checkpoint kinase TTK causes chromosome mis-segregation and tumor cell death. However, high levels of TTK correlate with chromosomal instability (CIN), which can lead to aneuploidy. We show that treatment of tumor cells with the selective small molecule TTK inhibitor NTRC 0066-0 overrides the mitotic checkpoint, irrespective of cell line sensitivity. In stable aneuploid cells NTRC 0066-0 induced acute CIN, whereas in cells with high levels of pre-existing CIN there was only a small additional fraction of cells mis-segregating their chromosomes. In proliferation assays stable aneuploid cells were more sensitive than cell lines with pre-existing CIN. Tetraploids are thought to be an intermediate between diploid and unstable aneuploid cells. TTK inhibitors had the same potency on post-tetraploid and parental diploid cells, which is remarkable because the post-tetraploids are more resistant to mitotic drugs. Finally, we confirm that the reference compound reversine is a TTK inhibitor and like NTRC 0066-0, inhibits the proliferation of patient-derived colorectal cancer organoids. In contrast, treatment with TTK inhibitor did not reduce the viability of non-proliferating T cell acute lymphoblastic leukemia cells samples. Consequently, TTK inhibitor therapy is expected to spare non-dividing cells, and may be used to target stable aneuploid tumors.
AB - Inhibition of the spindle assembly checkpoint kinase TTK causes chromosome mis-segregation and tumor cell death. However, high levels of TTK correlate with chromosomal instability (CIN), which can lead to aneuploidy. We show that treatment of tumor cells with the selective small molecule TTK inhibitor NTRC 0066-0 overrides the mitotic checkpoint, irrespective of cell line sensitivity. In stable aneuploid cells NTRC 0066-0 induced acute CIN, whereas in cells with high levels of pre-existing CIN there was only a small additional fraction of cells mis-segregating their chromosomes. In proliferation assays stable aneuploid cells were more sensitive than cell lines with pre-existing CIN. Tetraploids are thought to be an intermediate between diploid and unstable aneuploid cells. TTK inhibitors had the same potency on post-tetraploid and parental diploid cells, which is remarkable because the post-tetraploids are more resistant to mitotic drugs. Finally, we confirm that the reference compound reversine is a TTK inhibitor and like NTRC 0066-0, inhibits the proliferation of patient-derived colorectal cancer organoids. In contrast, treatment with TTK inhibitor did not reduce the viability of non-proliferating T cell acute lymphoblastic leukemia cells samples. Consequently, TTK inhibitor therapy is expected to spare non-dividing cells, and may be used to target stable aneuploid tumors.
KW - Aneuploidy
KW - Chromosome instability
KW - Kinase inhibitor
KW - Mps1
KW - TTK
UR - http://www.scopus.com/inward/record.url?scp=85020728821&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.16213
DO - 10.18632/oncotarget.16213
M3 - Article
AN - SCOPUS:85020728821
SN - 1949-2553
VL - 8
SP - 38309
EP - 38325
JO - Oncotarget
JF - Oncotarget
IS - 24
ER -