Page 107 - Read Online

Jia et al. Cancer Drug Resist 2019;2:210-24 I http://dx.doi.org/10.20517/cdr.2018.010 Page 219

Plk1, known as polo-like kinase 1, supports the functional maturation of the centrosome and establishment
of the bipolar spindle. Overexpression of Plk1 is often observed in cancer cells . This protein therefore
[121]
is a potential drug target in cancer . Several inhibitors of PLK1 have been developed and the promising
[122]
results have been obtained in clinical trials . For example, as compared to administration of cytarabine
[123]
(a chemotherapy medication used to treat acute myeloid leukemia ) alone, a combination of BI 6727 with
cytaribine increased the response with 31% total remission from 13% .
[124]
Cyclin-dependent kinases (Cdks) are a family of protein kinases that regulate the centrosome cycle but
deregulation of those Cdks by oncogenes and tumor supressors results to centrosome amplification . More
[125]
than 30 small-molecule inhibitors developed . Many of them have been used in clinical trials studies for
[126]
the treatment of various cancers [Table 2] . Flavopiridol is the first Cdk inhibitor used in clinical trials .
[127]
[128]
Flavopiridol has been successful in the treatment of AML and chronic lymphocytic leukemia [129,130] .
The Aurora kinases (AURKs) are involved in different aspects of mitotic control during cell cycle.
Importantly, PLK1 is activated by AURKA/B. Therefore AURKs are potential targets against centrosome
for cancer therapy. More than 30 AURK inhibitors have been developed and used in clinical studies . For
[131]
example, the inhibitor MLN8237 (alisertib), which targets AURKA, showed promising efficacy in several
solid tumors . AZD1152 (barasertib) is a selective inhibitor of AURKB and has been effective in AML
[132]
patients with an overall response rate of 25%, but with no effective results in patients with solid tumors.
In addition, AURKB/AURKC kinase inhibitor GSK1070916A is actually being tested in patients with solid
tumors and phase I in the clinical trial has been completed.

CONCLUSION
The consequences of numerical aberrations/centrosome amplification leading to tumorigenesis have been
studied extensively. In contrast, studies on mechanisms of cancer drug resistance in relation to centrosome
aberrations have received little attention. Epigenetic modifications in centrosome biogenesis have important
implications for the origin of some malignant tumors and play a role in cancer drug resistance. The current
review discussed the connection of epigenetic changes causing centrosome aberrations to cancer drug
resistance. For clinical, the ultimate goal is to identify effective cancer therapy. So far, most of clinical trials
targeting possible drug resistance, which were registered to ClinicalTrials.gov at NIH are still monotherapies
and in early stages of development. One important factor we should not forget is that regulation pathways
to epigenetic modifications of centrosome, such as positive or negative feedback signaling circuits involved
in cancer drug resistance are more complex than once thought. The selection of drugs, together with other
treatment like immunotherapy, for combination therapy may lead to improve efficacy and to thwart drug
resistance. In the future, one need to address molecular mechanisms how the trafficking of centrosome
proteins between centrosome and nucleus determine expression/subcellular localization of downstream
signaling molecules, such as the Bcl2 family proteins and ABC transporters. Further understanding of
centrosome biology including basic cell biology or pathobiology of epigenetic controls in centrosome will
provide potential to establish translatable strategies for cancer treatment and to prevent drug resistance.

DECLARATIONS
Authors’ contributions
Conception: Jia ZH, Wang XG, Zhang H
Design of the study: Jia ZH, Wang XG, Zhang H
Wrote: Jia ZH, Wang XG, Zhang H

Availability of data and materials
Not applicable.