Zhang, Yi-Xiang, Sicinska, Ewa, Czaplinski , Jeffrey, Remillard, Stephen, Moss, Samuel, Wang, Yuchuan, Brain, Christopher, Loo, Alice, Snyder, Eric, Demetri, George, Kim, Sunkyu, Kung, Andrew and Wagner, Andrew (2014) Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo. Molecular Therapeutics.

Abstract

Purpose:
Well-differentiated/dedifferentiated liposarcomas (WD/DDLPS) are characterized by chromosomal amplification of 12q13-15, a region containing the cyclin-dependent-kinase 4 (CDK4) oncogene. We explored the role of CDK4 and the effects of LEE011, a novel selective inhibitor of CDK4/CDK6, on human liposarcoma cell lines and primary tumor xenografts.
Experimental Design:
CDK4 small interfering RNA (siRNA) or LEE011 was applied to liposarcoma cell lines and changes in biochemical signaling, cell cycle, and cell growth were determined. Cells were transfected with retinoblastoma protein (RB) siRNA to determine the specificity of the effects of LEE011. In vivo antiproliferative and antimetabolic effects of LEE011 were evaluated in cell line and primary tumor xenograft models of WD/DDLPS.
Results:
Both CDK4 knockdown by siRNA and inhibition by LEE011 diminished RB phosphorylation and dramatically decreased liposarcoma cell growth. Cell cycle analysis demonstrated arrest at G0/G1. siRNA-mediated knockdown of RB rescued the inhibitory effects of LEE011, demonstrating that LEE011 decreased proliferation through RB. Oral administration of LEE011 to mice bearing human liposarcoma xenografts resulted in approximately 50% reduction in tumor 18F- fluorodeoxyglucose uptake with dramatically decreased tumor biomarkers including RB phosphorylation and bromodeoxyuridine incorporation in vivo. Continued treatment inhibited tumor growth or induced regression without detrimental effects on mouse weight. After prolonged continuous dosing, reestablishment of RB phosphorylation and cell cycle progression was noted.
Conclusions:
LEE011 potently decreases cell cycle progression, hypermetabolism, and proliferation of human liposarcomas in an RB-dependent manner, consistent with inhibition of CDK4. Translational application in clinical trials of LEE011 in patients with CDK4-amplified liposarcoma is warranted.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/20509