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When a cell divides, a scaffold of microtubules (the spindle) pulls one copy of each chromosome to each side. A checkpoint holds the split until every chromosome is hooked on. Taxanes and vinca alkaloids freeze the spindle so the cell is stuck at this checkpoint until it dies.
In prometaphase, unattached kinetochores recruit MPS1, MAD1/MAD2, BUB1/BUBR1 to assemble the mitotic checkpoint complex, which inhibits APC/C-CDC20, keeping securin and cyclin B intact so anaphase cannot start. Once all kinetochores are attached under tension (Aurora B corrects mis-attachments), the checkpoint silences, separase cleaves cohesin, and chromosomes segregate; PLK1 and Aurora A drive spindle assembly and centrosome maturation, KIF18A tames chromosome oscillation. Microtubule drugs (taxanes, epothilones, eribulin stabilise or sequester; vinca alkaloids and ADC payloads MMAE/DM1 destabilise) cause persistent checkpoint activation; cells either die in mitosis (BCL-XL degradation, MCL-1 loss) or 'slip' into a tetraploid G1 where p53 arrests them, which is why TP53 loss tolerates slippage and drives aneuploidy. Whole-genome doubling and chromosomal instability arise here; CIN-high tumours depend on KIF18A, the checkpoint and BCL-XL. Aurora, PLK1 and MPS1 inhibitors have narrow windows; alisertib is being retested in SCLC and neuroendocrine prostate cancer.
A tug-of-war where the referee (spindle checkpoint) will not blow the whistle until every player has a grip on the rope. Taxanes glue the rope so nobody can pull; the match never starts and the players eventually collapse. Cells without p53 sneak off the pitch with the wrong number of players, which is how aneuploidy begins.
It was the first evidence that neuroendocrine prostate cancer is a distinct molecular disease with its own candidate drug target, and it started the programme of Aurora kinase trials in this setting, which have since disappointed.
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