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Breast Cancer Research
Published in: Breast Cancer Research 5/2009

Open Access 01-10-2009 | Research article

PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro

Authors: Richard S Finn, Judy Dering, Dylan Conklin, Ondrej Kalous, David J Cohen, Amrita J Desai, Charles Ginther, Mohammad Atefi, Isan Chen, Camilla Fowst, Gerret Los, Dennis J Slamon

Published in: Breast Cancer Research | Issue 5/2009

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Abstract

Introduction

Alterations in cell cycle regulators have been implicated in human malignancies including breast cancer. PD 0332991 is an orally active, highly selective inhibitor of the cyclin D kinases (CDK)4 and CDK6 with ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. To identify predictors of response, we determined the in vitro sensitivity to PD 0332991 across a panel of molecularly characterized human breast cancer cell lines.

Methods

Forty-seven human breast cancer and immortalized cell lines representing the known molecular subgroups of breast cancer were treated with PD 0332991 to determine IC50 values. These data were analyzed against baseline gene expression data to identify genes associated with PD 0332991 response.

Results

Cell lines representing luminal estrogen receptor-positive (ER+) subtype (including those that are HER2 amplified) were most sensitive to growth inhibition by PD 0332991 while nonluminal/basal subtypes were most resistant. Analysis of variance identified 450 differentially expressed genes between sensitive and resistant cells. pRb and cyclin D1 were elevated and CDKN2A (p16) was decreased in the most sensitive lines. Cell cycle analysis showed G0/G1 arrest in sensitive cell lines and Western blot analysis demonstrated that Rb phosphorylation is blocked in sensitive lines but not resistant lines. PD 0332991 was synergistic with tamoxifen and trastuzumab in ER+ and HER2-amplified cell lines, respectively. PD 0332991 enhanced sensitivity to tamoxifen in cell lines with conditioned resistance to ER blockade.

Conclusions

These studies suggest a role for CDK4/6 inhibition in some breast cancers and identify criteria for patient selection in clinical studies of PD 0332991.
Appendix
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Metadata
Title
PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro
Authors
Richard S Finn
Judy Dering
Dylan Conklin
Ondrej Kalous
David J Cohen
Amrita J Desai
Charles Ginther
Mohammad Atefi
Isan Chen
Camilla Fowst
Gerret Los
Dennis J Slamon
Publication date
01-10-2009
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 5/2009
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2419

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