{"entity":{"id":"mitotic-spindle-checkpoint","kind":"pathway","name":"Mitosis & the spindle assembly checkpoint","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Spindle_checkpoint","links":[{"label":"Musacchio & Salmon, The spindle-assembly checkpoint in space and time (Nat Rev Mol Cell Biol 2007)","url":"https://doi.org/10.1038/nrm2163"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","adc"],"targets":["her2","nectin4","cd30","folr1","bcl2","tp53"],"drugs":["paclitaxel","docetaxel","cabazitaxel","eribulin","vincristine","vinblastine","vinorelbine","trastuzumab-emtansine","enfortumab-vedotin","brentuximab-vedotin","mirvetuximab-soravtansine"],"companies":[],"institutions":[],"pathways":["chromosomal-instability","cell-cycle-engine-cdks","p53-cell-cycle","apoptosis-bcl2"],"terms":["tubulin-inhibitor-payloads","mmae","dm1","dm4","whole-genome-doubling"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-musacchio-nat-rev-mol-cell-biol"],"journals":[],"dependsOn":[],"notes":[],"analogy":"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.","nodes":[{"id":"cent","label":"Centrosomes (Aurora A, PLK1)","x":12,"y":15},{"id":"spin","label":"Spindle microtubules","x":40,"y":15},{"id":"kin","label":"Kinetochore attachment","x":68,"y":15},{"id":"tax","label":"Taxanes, vincas, MMAE, DM1","x":40,"y":45,"targetId":"her2"},{"id":"sac","label":"SAC: MAD2, BUBR1, MPS1","x":68,"y":45},{"id":"apc","label":"APC/C-CDC20","x":90,"y":45},{"id":"ana","label":"Anaphase (separase)","x":90,"y":78},{"id":"death","label":"Mitotic death (BCL-XL↓)","x":60,"y":78,"targetId":"bcl2"},{"id":"slip","label":"Slippage → tetraploid","x":30,"y":78},{"id":"p53","label":"p53 arrest","x":8,"y":78,"targetId":"tp53"}],"edges":[{"from":"cent","to":"spin","type":"activates"},{"from":"spin","to":"kin","type":"activates"},{"from":"tax","to":"spin","type":"inhibits"},{"from":"kin","to":"sac","type":"inhibits"},{"from":"sac","to":"apc","type":"inhibits"},{"from":"apc","to":"ana","type":"activates"},{"from":"sac","to":"death","type":"activates"},{"from":"sac","to":"slip","type":"activates"},{"from":"p53","to":"slip","type":"inhibits"}],"interventions":["Taxanes (paclitaxel, docetaxel, cabazitaxel), eribulin, vinca alkaloids (vincristine, vinblastine, vinorelbine)","Tubulin-payload ADCs: MMAE (enfortumab, brentuximab, polatuzumab vedotin), DM1 (T-DM1), DM4 (mirvetuximab)","Aurora A (alisertib), PLK1 and MPS1 inhibitors; KIF18A inhibitors for CIN-high tumours (trials)","BCL-XL degraders to tip arrested cells into death"]},"route":"/pathways/mitotic-spindle-checkpoint/","neighbours":{"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"}],"target":[{"id":"apc","kind":"target","name":"APC","route":"/targets/apc/"},{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"bub1","kind":"target","name":"BUB1","route":"/targets/bub1/"},{"id":"bub1b","kind":"target","name":"BUB1B","route":"/targets/bub1b/"},{"id":"cd30","kind":"target","name":"CD30","route":"/targets/cd30/"},{"id":"folr1","kind":"target","name":"Folate receptor alpha","route":"/targets/folr1/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"ttk","kind":"target","name":"MPS1 (TTK)","route":"/targets/ttk/"},{"id":"mxi1","kind":"target","name":"MXI1","route":"/targets/mxi1/"},{"id":"nectin4","kind":"target","name":"Nectin-4","route":"/targets/nectin4/"},{"id":"plk1","kind":"target","name":"PLK1","route":"/targets/plk1/"},{"id":"rps27","kind":"target","name":"RPS27","route":"/targets/rps27/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"brentuximab-vedotin","kind":"drug","name":"Brentuximab vedotin","route":"/drugs/brentuximab-vedotin/"},{"id":"cabazitaxel","kind":"drug","name":"Cabazitaxel","route":"/drugs/cabazitaxel/"},{"id":"docetaxel","kind":"drug","name":"Docetaxel","route":"/drugs/docetaxel/"},{"id":"enfortumab-vedotin","kind":"drug","name":"Enfortumab vedotin","route":"/drugs/enfortumab-vedotin/"},{"id":"eribulin","kind":"drug","name":"Eribulin","route":"/drugs/eribulin/"},{"id":"mirvetuximab-soravtansine","kind":"drug","name":"Mirvetuximab soravtansine","route":"/drugs/mirvetuximab-soravtansine/"},{"id":"paclitaxel","kind":"drug","name":"Paclitaxel / nab-paclitaxel","route":"/drugs/paclitaxel/"},{"id":"trastuzumab-emtansine","kind":"drug","name":"Trastuzumab emtansine","route":"/drugs/trastuzumab-emtansine/"},{"id":"vinblastine","kind":"drug","name":"Vinblastine","route":"/drugs/vinblastine/"},{"id":"vincristine","kind":"drug","name":"Vincristine","route":"/drugs/vincristine/"},{"id":"vinorelbine","kind":"drug","name":"Vinorelbine","route":"/drugs/vinorelbine/"}],"pathway":[{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"id":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","route":"/pathways/apoptosis-bcl2/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"cell-cycle-engine-cdks","kind":"pathway","name":"The cell-cycle engine (cyclins & CDKs)","route":"/pathways/cell-cycle-engine-cdks/"}],"term":[{"id":"aneuploidy-theory-of-cancer","kind":"term","name":"Aneuploidy and chromosomal instability as the cause of cancer","route":"/terms/aneuploidy-theory-of-cancer/"},{"id":"checkpoint","kind":"term","name":"Checkpoint (two meanings)","route":"/terms/checkpoint/"},{"id":"dm1","kind":"term","name":"DM1","route":"/terms/dm1/"},{"id":"dm4","kind":"term","name":"DM4","route":"/terms/dm4/"},{"id":"mmae","kind":"term","name":"MMAE","route":"/terms/mmae/"},{"id":"tubulin-inhibitor-payloads","kind":"term","name":"Tubulin inhibitor payloads","route":"/terms/tubulin-inhibitor-payloads/"},{"id":"whole-genome-doubling","kind":"term","name":"Whole-genome doubling (WGD)","route":"/terms/whole-genome-doubling/"}],"paper":[{"id":"paper-beltran-nepc-aurka-mycn-cancer-discov-2011","kind":"paper","name":"Molecular characterisation of neuroendocrine prostate cancer and identification of new drug targets","route":"/key-papers/paper-beltran-nepc-aurka-mycn-cancer-discov-2011/"},{"id":"paper-musacchio-nat-rev-mol-cell-biol","kind":"paper","name":"The spindle-assembly checkpoint in space and time","route":"/key-papers/paper-musacchio-nat-rev-mol-cell-biol/"}]}}