Expression levels of p18INK4C modify the cellular efficacy of cyclin-dependent kinase inhibitors via regulation of Mcl-1 expression in tumor cell lines
Because cyclin-dependent kinases (CDK) play a pivotal role in cancer progression, the development of CDK inhibitors has attracted attention in antitumor therapy. However, despite significant preclinical and clinical developments, CDK inhibition biomarkers for predicting efficacy against certain canc...
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Published in | Molecular cancer therapeutics Vol. 8; no. 6; pp. 1460 - 1472 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research
01.06.2009
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Subjects | |
Online Access | Get full text |
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Summary: | Because cyclin-dependent kinases (CDK) play a pivotal role in cancer progression, the development of CDK inhibitors has attracted
attention in antitumor therapy. However, despite significant preclinical and clinical developments, CDK inhibition biomarkers
for predicting efficacy against certain cancers in individual patients have not been identified. Here, we characterized a
macrocyclic quinoxalin-2-one CDK inhibitor, compound A, and identified a gene biomarker for predicting its efficacy. Compound
A showed 100-fold selectivity for CDK family proteins over other kinases and inhibited both E2F transcriptional activity and
RNA polymerase II phosphorylation. Compound A treatment resulted in decreased proliferation in various tumor cell lines; however,
the apoptosis induction rate differed significantly among the cell lines examined, which was consistent with roscovitine.
By comparing the mRNA expression profiles of sensitive and resistant cell lines, we found that expression levels of an endogenous
CDK inhibitor, p18 INK4C , showed a strong negative correlation to the sensitivity. In fact, p18 status was correlated with the response to CDK inhibitor
in an independent data set of multiple myeloma cell lines and silencing p18 expression increased the susceptibility of resistant
cells to CDK inhibitors. The analysis of molecular mechanisms revealed that cells with lowered p18 had aberrant CDK6 and E2F
activities, which resulted in a transcriptional down-regulation of Mcl-1, a key molecule associated with flavopiridol-induced
apoptosis, thereby leading to susceptibility to therapeutic intervention with CDK inhibitors. These results identified a molecular
basis for CDK inhibitors to exert an antitumor effect in p18-deficient cancers and support the clinical use of CDK inhibitors.
[Mol Cancer Ther 2009;8(6):1460–72] |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-08-1159 |