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AMG 900, pan-Aurora kinase inhibitor, preferentially inhibits the proliferation of breast cancer cell lines with dysfunctional p53
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AMG 900, pan-Aurora kinase inhibitor, preferentially inhibits the proliferation of breast cancer cell lines with dysfunctional p53
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Journal Article
AMG 900, pan-Aurora kinase inhibitor, preferentially inhibits the proliferation of breast cancer cell lines with dysfunctional p53
2013
Overview
Aurora kinases play important roles in cell division and are frequently overexpressed in human cancer. AMG 900 is a novel pan-Aurora kinase inhibitor currently being tested in Phase I clinical trials. We aimed to evaluate the in vitro activity of AMG 900 in a panel of 44 human breast cancer and immortalized cell lines and identify predictors of response. AMG 900 inhibited proliferation at low nanomolar concentrations in all cell lines tested. Response was further classified based on the induction of lethality. 25 cell lines were classified as highly sensitive (lethality at 10 nM of AMG 900 >10 %), 19 cell lines as less sensitive to AMG 900 (lethality at 10 nM of AMG 900 <10 %). Traditional molecular subtypes of breast cancer did not predict for this differential response. There was a weak association between
AURKA
amplification and response to AMG 900 (response ratio = 2.53,
p
= 0.09). mRNA expression levels of
AURKA
,
AURKB
, and
AURKC
and baseline protein levels of Aurora kinases A and B did not significantly associate with response. Cell lines with
TP53
loss of function mutations (RR = 1.86,
p
= 0.004) and low baseline p21 protein levels (RR = 2.28,
p
= 0.0004) were far more likely to be classified as highly sensitive to AMG 900. AMG 900 induced p53 and p21 protein expression in cell lines with wt
TP53
. AMG 900 caused the accumulation of cells with >4 N DNA content in a majority of cell lines independently of sensitivity and p53 status. AMG 900 induced more pronounced apoptosis in highly sensitive p53-dysfunctional cell lines. We have found that AMG 900 is highly active in breast cancer cell lines and that
TP53
loss of function mutations as well as low baseline expression of p21 protein predict strongly for increased sensitivity to this compound in vitro.
Publisher
Springer US,Springer,Springer Nature B.V
Subject
Antineoplastic Agents - pharmacology
/ Aurora Kinase A - antagonists & inhibitors
/ Aurora Kinase A - metabolism
/ Aurora Kinase B - antagonists & inhibitors
/ Aurora Kinase B - metabolism
/ Aurora Kinase C - antagonists & inhibitors
/ Aurora Kinase C - metabolism
/ Biological and medical sciences
/ Cell Proliferation - drug effects
/ Cyclin-Dependent Kinase Inhibitor p21 - metabolism
/ Drug Screening Assays, Antitumor
/ Female
/ Gynecology. Andrology. Obstetrics
/ Humans
/ Kinases
/ Medicine
/ Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
/ Mutation
/ Oncology
/ RNA
/ Tumor Suppressor Protein p53 - genetics
/ Tumor Suppressor Protein p53 - metabolism
/ Tumors
