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
Open Access
- 29 October 2009
- journal article
- Published by Springer Science and Business Media LLC in Breast Cancer Research
- Vol. 11 (5), R77
- https://doi.org/10.1186/bcr2419
Abstract
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. 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. 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. 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.Keywords
This publication has 48 references indexed in Scilit:
- Cancer Statistics, 2008CA: A Cancer Journal for Clinicians, 2008
- Abrogated Response to Cellular Stress Identifies DCIS Associated with Subsequent Tumor Events and Defines Basal-like Breast TumorsCancer Cell, 2007
- Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitroBreast Cancer Research and Treatment, 2007
- A collection of breast cancer cell lines for the study of functionally distinct cancer subtypesCancer Cell, 2006
- Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activityBlood, 2006
- Cyclin-Dependent Kinase 4 Expression Is Essential for Neu-Induced Breast TumorigenesisCancer Research, 2005
- Breast cancer classification and prognosis based on gene expression profiles from a population-based studyProceedings of the National Academy of Sciences of the United States of America, 2003
- Prognostic value of combined analysis of cyclin D1 and estrogen receptor status in breast cancer patientsPathology International, 2003
- Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implicationsProceedings of the National Academy of Sciences of the United States of America, 2001
- The Hallmarks of CancerCell, 2000