Reference Detail

Ref Type

Journal Article

PMID

(19874578)

Authors

Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Breast cancer research : BCR	11	5	2009	R77	Breast Cancer Res

URL

Abstract Text

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

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Palbociclib	Palbociclib	46	52
Palbociclib + Vemurafenib	Palbociclib Vemurafenib	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Palbociclib	Ibrance	PD0332991\|PD-0332991	CDK4/6 Inhibitor 13	Ibrance (palbociclib) is a selective inhibitor of cyclin-dependent kinase 4 (CDK4) and 6 (CDK6) (PMID: 19874578). Ibrance (palbociclib) is approved in combination with an aromatase inhibitor in postmenopausal patients with ER-positive, ERBB2 (HER2)-negative metastatic breast cancer, and in combination with Faslodex (fulvestrant) in patients with ER-positive, ERBB2 (HER2)-negative metastatic breast cancer (FDA.gov).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References