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

Abstract

PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC50, 0.011 μmol/L) and Cdk6 (IC50, 0.016 μmol/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.

CDK4/6 Inhibitors in Combination Therapies: Better in Company Than Alone: A Mini Review

“…Tumors expressing ER and/or PR are termed hormone receptor positive (HR+) or luminal BC, accounting for over 70% of all BC; tumors expressing HER2 are called HER2-enriched BC, accounting for 10-20% of BC; and tumors that do not express ER, PR and HER2 are called triple negative (TN) BC, accounting for 10-15% of BC ( 30 , 73 ). When CDK4/6i were developed and tested in preclinical studies, cell lines and xenografts representing the luminal BC subtype were shown to be most susceptible to proliferation arrest and tumor shrinkage ( 31 , 74 ).…”

Chemoproteomic Evaluation of Target Engagement by the Cyclin-Dependent Kinase 4 and 6 Inhibitor Palbociclib Correlates with Cancer Cell Response

“…In order to assess the general selectivity of palbociclib, we profiled it in lysates derived from the COLO-205 cell line, a cell line known to be sensitive. 11 The profiling was carried out at 10, 1, 0.1, and 0.01 μM, and the results are displayed as a waterfall plot in Figure 3A. The most potent targets are shown in the inset of the waterfall plot, together with the estimated IC 50 values.…”

“…COLO-205 cells are sensitive to palbociclib (DNA replication inhibition IC 50 0.13 μM), while MDA-MB-468 cells are resistant (DNA replication inhibition IC 50 > 3 μM). 11 After treatment of the cells with compound, cells were harvested, lysed, probe-labeled, and analyzed by mass spectrometry. The goal of this approach was to evaluate the kinase profiles between the two cells lines in order to understand why COLO-205 cells are sensitive and MDA-MB-468 cells resistant to palbociclib.…”

“…To address this possibility, we profiled palbociclib in lysates derived from COLO-205 and MDA-MB-468 head-to-head. In addition, we also profiled palbociclib in two more cell lines, MCF7 (sensitive) 11,14 and BT549 (resistant). 14 The IC 50 values for the inhibition of CDK4 and CDK6 are shown in Figure 5.…”

“…9,10 Palbociclib (PD0332991, Ibrance) inhibits recombinant CDK4 and CDK6 with IC 50 's in the 0.01−0.02 μM range and displays good efficacy in inducing G1 arrest in a number of Rb positive cells. 11,12 It has recently been approved for estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer, 13 with clinical trials underway for non-small-cell lung cancer, as well as other solid tumors that are metastatic or cannot be removed by surgery. Due to the inherent complexity of cell cycle progression, predicting responsiveness to palbociclib remains challenging.…”