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
By R. Finn, J. Dering, D. Conklin, O. Kalous, David J Cohen, Amrita J. Desai, C. Ginther, M. Atefi, I. Chen, C. Fowst and 2 more. Breast Cancer Research, 2009
1,330 citations recorded by the source corpus.
IntroductionAlterations 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.MethodsForty-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.ResultsCell 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.ConclusionsThese studies suggest a role for CDK4/6 inhibition in some breast cancers and identify criteria for patient selection in clinical studies of PD 0332991.
Subfields: Oncology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/7ae72ec5530025ffaffb38472257172aedb9860e
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Citations in the corpus
- Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer (2016, positive): “S1E), as anticipated through palbociclib-arresting cells in G0–G1 (21).”
- Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer (2018, neutral): “Gemcitabine 7 (3) 6 (3) 26 (20) 5 (4) 9 (8) 15 (18)”
- Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets (2015, background): “Alterations potentially predicting sensitivity to CDK inhibitors (31-33) were common across our case series, with 71 alterations in 48 cases occurring in 10 of 11 evaluated genes (Fig.”
- Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis (2018, background): “The oral CDK4/6 inhibitor Palbocyclib alone was shown to inhibit cell cycle progression ER-positive cell lines, including those with HER2 amplification, which were most sensitive to growth inhibition by palbocyclib while nonluminal/basal subtypes were most resistant.(91) Thus, Palbocyclib is a promi”