Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts.

By D. W. Fry, P. Harvey, P. Keller, W. Elliott, M. Meade, E. Trachet, M. Albassam, Xianxian Zheng, W. Leopold, N. Pryer and 1 more. Molecular Cancer Therapeutics, 2004

1,210 citations recorded by the source corpus.

PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC50, 0.011 micromol/L) and Cdk6 (IC50, 0.016 micromol/L), having no activity against a panel of 36 additional protein kinases. It is a potent antiproliferative agent against retinoblastoma (Rb)-positive tumor cells in vitro, inducing an exclusive G1 arrest, with a concomitant reduction of phospho-Ser780/Ser795 on the Rb protein. Oral administration of PD 0332991 to mice bearing the Colo-205 human colon carcinoma produces marked tumor regression. Therapeutic doses of PD 0332991 cause elimination of phospho-Rb and the proliferative marker Ki-67 in tumor tissue and down-regulation of genes under the transcriptional control of E2F. The results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors.

Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/74f3422c2c574d17419b4e2da76299231d4d3196

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In Molecular Biology

1. Eric S. Lander
2. Gad Getz
3. Matthew Meyerson
4. G. Shapiro
5. William C. Hahn
6. Levi A. Garraway
7. Scott L. Carter
8. Stacey Gabriel

In Oncology

1. William C. Hahn
2. G. Shapiro
3. C. Sherr
4. J. Baselga
5. J. Seoane
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7. D. Louis
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In Pulmonary and Respiratory Medicine

1. J. Baselga

Citations in the corpus

• 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 (2009, background): “PD 0332991 is an orally active potent and highly selective inhibitor of CDK4 and CDK6 kinases, which in low nanomolar concentrations blocks pRb phosphorylation - subsequently inducing G1 arrest in sensitive cell lines [26-29].”
• Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets (2015, background): “In addition, five cases had shared homozygous RB1 loss, which is associated with resistance to CDK inhibitors (35).”
• Cyclin D-CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance (2017, neutral): “Rb is frequently inactivated in human cancers 18,19 .”
• Cyclin-dependent kinase pathways as targets for cancer treatment. (2006, background): “carcinoma xenografts, PD 0332991 produced rapid tumor regression.(73) It is possible that the tumor represents a balance of proliferating”