[Cell Cycle 5:8, 818-823, 15 April 2006]; ©2006 Landes Bioscience
Chromosomal Instability, Colorectal Cancer and Taxane Resistance Perspective
ABSTRACT
*Correspondence to: Charles Swanton; Signal Transduction Laboratory; Cancer Research UK London Research Institute; 44 Lincoln’s Inn Fields; London WC2A 3PX UK; Tel.: +00.44.207.269.3431; Fax: +00.44.207.269.3094; Email:
[email protected] Original manuscript submitted: 02/16/06 Manuscript accepted: 03/06/06
Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2682
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chromosomal instability anaphase promoting complex adenomatous polyposis coli budding uninhibited by benzimidazole colorectal cancer kinesin 5 inhibitor mitotic arrest deficient monopolar spindle microtubule inhibitor microsatellite instability
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In the era of targeted therapies and patient selection based on expression of biological markers, attempts to define patient subgroups with an increased likelihood of response to traditional chemotherapeutic agents must not be overlooked. The taxanes have an established and important role in the management of metastatic breast and ovarian cancer with response rates ranging from 15–60% in the first line setting. There is also a clinical role for taxanes in the management of other solid tumors such as prostate and upper gastrointestinal malignancies. There has been no clear explanation, however, why patients treated in early phase I/II studies in colorectal cancer (CRC) have failed to derive a significant clinical benefit following treatment with the two commonest taxanes, paclitaxel or docetaxel. Published data have established that molecules which regulate the spindle checkpoint antagonise taxane activity in vitro when overexpressed (e.g., Aurora Kinase A) or when targeted by RNA interference oligonucleotides (siRNAs) (e.g., BubR1, Mad2).1-4 Genetic aberrations in key molecules, such as BubR1, Bub1 and members of the Aurora kinase family also promote chromosomal instability (CIN) as well as resistance to MTIs such as paclitaxel, nocodazole or vincristine (Table 1). Recent published data also suggest that the adenomatous polyposis coli gene product, APC (commonly mutated in patients with CRC harbouring CIN) plays a role at the spindle checkpoint and that APC mutations in CRCs can impair a mitotic arrest by microtubule targeted agents. These observations support the hypothesis that a functional spindle checkpoint is required for an efficient taxane response and for maintenance of chromosomal stability. Conversely, in a minority of CRCs (
