Chromosomal instability, colorectal cancer and taxane resistance.
The spindle checkpoint monitors the fidelity of chromosome separation during mitosis. Aberrations in key regulators of this process have been found in human malignancies associated with chromosomal instability (CIN). Important chemotherapeutic agents which alter microtubule dynamics such as paclitaxel and vincristine, prolong spindle checkpoint activation and delay the completion of mitosis. Intriguingly, inhibition of BubR1 or overexpression of Aurora kinase A, spindle checkpoint regulators implicated in CIN, promote resistance to microtubule inhibitors (MTIs) in vitro. Taxanes have failed to demonstrate significant clinical benefit in phase II trials in colorectal cancer (CRC). The high incidence of CIN in this disease, coupled with alterations in spindle checkpoint regulators in vivo, may explain the disappointing results associated with taxane based therapies for CRC. A phase II trial of taxanes in patients with metastatic CIN negative CRC may be indicated.
Swanton
Charles
C
Royal Marsden Hospital, Department of Medicine, London, UK. charles.swanton@cancer.org.uk
Tomlinson
Ian
I
Downward
Julian
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D064096:Aurora Kinase A; D064127:Aurora Kinases; D043171:Chromosomal Instability; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D008941:Spindle Apparatus; D043823:Taxoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D043823:Taxoids; D014750:Vincristine; D011494:Protein Kinases; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel