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

Richard S Finn¹ , Judy Dering¹ , Dylan Conklin¹ , Ondrej Kalous¹ , David J Cohen¹ , Amrita J Desai¹ , Charles Ginther¹ , Mohammad Atefi¹ , Isan Chen² , Camilla Fowst³ , Gerret Los² and Dennis J Slamon¹

¹  Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, 10833 Le Conte Ave, 11-934 Factor Bldg, Los Angeles, CA 90095, USA

²  Pfizer Global Research and Development, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA

³  Pfizer Oncology BU, Clinical Development, Pfizer Inc., Via Lorenteggio 257, Milan 20152, Italy

author email corresponding author email

Breast Cancer Research 2009, 11:R77doi:10.1186/bcr2419

Published:	29 October 2009

See related editorial by Sutherland and Musgrove, http://breast-cancer-research.com/content/11/6/112

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.