Biology Reference
In-Depth Information
15.11 Therapeutic Implications of Centrosome Amplification
in Multiple Myeloma
Besides being a prognostic marker, centrosome amplification (or a surrogate like the
CI) may also serve as a therapeutic marker in MM. As proof of concept, we showed
that HMCL with higher CI were more sensitive to a small molecular Aurora kinase
inhibitor (MLN8054) (Chng et al.
2008
). Although it can be argued that a more direct
marker for sensitivity to Aurora A inhibition might be expression levels of the
Aurora-A gene/protein itself, it is noteworthy that Aurora A is regulated both at the
expression level as well as via the phosphorylation of T288 on its activation loop
(Dar et al.
2010
). Therefore, expression levels of Aurora-A alone as a predictive
therapeutic marker might not be optimal; in theory, a downstream marker of Aurora-
A activity, such as centrosome amplification, might be of greater utility.
Centrosome amplification in MM might also be a therapeutic marker for other
established or potential targets, such as TOP2A or PLK4, both of which were
upregulated in high CI MM in our study (Chng et al.
2008
). The Polo-like kinases
(Plks, of which Plk4 is a member) are particularly attractive in this regard, as they
have known roles in centrosome function (Dai et al.
2002
), and overexpression of
Plk1 in vitro also results in numerical centrosomal abnormalities (Meraldi et al.
2002
). The role of the Plks in MM pathogenesis is still not well-characterized, but
at least one study has shown activity of a Plk small molecular inhibitor against
MM cell lines (Stewart et al.
2011
).
Another recently proposed therapeutic strategy involves disrupting centrosome
clustering (Fielding et al.
2011
), which as previously mentioned is a protective
mechanism preventing multipolar mitoses and cell death in cells with supernu-
merary centrosomes (Kwon et al.
2008
; Quintyne et al.
2005
). In a proof of
concept study, Fielding et al. showed that integrin-linked kinase (ILK) is required
for centrosome clustering in breast and prostate cancer cells. Furthermore, phar-
macological inhibition of ILK led to multipolar divisions and cell death, and the
sensitivity of the cell lines to ILK inhibition correlated with centrosome number
(Fielding et al.
2011
). Interestingly, another recent study reported that pharma-
cological ILK inhibition led to apoptosis in HMCL (Wang et al.
2010
). Further
studies investigating a correlation between sensitivity to ILK inhibition and cen-
trosome abnormalities in MM are warranted.
15.12 Future Perspectives
Although some progress has been made concerning the role of centrosomes in MM
biology and pathogenesis, the molecular pathways and mechanisms by which
centrosome amplification and clustering occur in MM remain poorly character-
ized. Table
15.1
provides a list of molecules that may represent candidates for
further study in the biology of centrosome abnormalities in MM. Also, in view of
