Chromosome segregation errors: a double-edged sword - TI Pharma

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of checkpoint function can be achieved in clinical settings. Nonetheless, partial inhibition of mitotic
checkpoint function combined with an approach that perturbs proper chromosome alignment
could enhance chromosome segregation errors above the threshold required to kill tumor cells.
In line with this, work from our own lab has shown that partial mitotic checkpoint inhibition in
combination with sub-lethal doses of paclitaxel can produce a synergistic effect in tumor cell
death that is not observed in non-transformed cells 299 (Fig.3). Inhibition of centrosome clustering,
as mentioned above, could be another approach to enhance chromosome segregation errors in
CIN cells harboring multiple centrosomes (Fig.2). The multipolarity resulting from this strategy
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A) Mitotic exit without inhibitors
Normal cells CIN tumor cells
B) Mitotic exit + (partial) Mitotic checkpoint inhibition + chromosome misalignments
Normal cells CIN tumor cells
Diploid offspring Aneuploid offspring
Normal
cell cycle progression
M
G1
G2
S
Tumorigenesis Cell cycle
arrest
STOP
Cell death
Severely aneuploid offspring
Cell death
Figure 3. Model for mitotic checkpoint inhibition as a specific anti-CIN cancer strategy
A) Chromosomally unstable (CIN) tumor cells often missegregate chromosomes upon mitotic exit when compared to healthy
proliferating cells. B) Enhancing chromosome alignment defects in combination with (partial) mitotic checkpoint inhibition will
result in severe chromosome missegregations in CIN tumor cells and promote cell death. In contrast, in normal healthy cells (partial)
mitotic checkpoint inhibition can lead to two alternative outcomes: the cell division is unaffected and cells exit mitosis normally,
resulting in healthy diploid daughter cells, or aneuploid progeny is produced. This progeny has a high probability to either arrest or
die. Some aneuploid daughter cells could escape the cell cycle arrest and might eventually become tumorigenic.