Abstract A236: Human liposarcoma growth inhibition by novel CDK4/6 inhibitor LEE011.

Abstract

Abstract Background: Well-differentiated and de-differentiated liposarcomas (WD/DDLPS) are characterized by high-level chromosomal amplification of 12q13–15, a region including the cyclin-dependent kinase 4 (CDK4) oncogene. In this study, we explored the effects of LEE011, a novel selective inhibitor of CDK4/CDK6 on human liposarcoma cell lines and primary tumor xenografts. Materials and Methods: We examined the expression of cell cycle regulatory proteins in human liposarcoma cell lines and human normal preadipocytes/adipocytes. CDK4 small interfering RNA (siRNA) or LEE011 was applied to liposarcoma cell lines and the biological consequences were determined by phospho-RB immunoblot, cell cycle assay and cell enumeration. In addition, liposarcoma cells were transfected with RB siRNA to determine the specificity of the effects of LEE011. Nude mice implanted with human liposarcoma cell lines or primary tumors were treated with LEE011 or vehicle by oral gavage. After 3 daily doses, in vivo BrdU incorporation assay, immunostains for phospho-RB, and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan were performed. Tumor size and animal weight were serially measured during 3 weeks of dosing. Results: CDK4 and p-Rb are highly expressed in human liposarcoma cell lines in comparison with normal preadipocytes/adipocytes. Both CDK4 siRNA and LEE011 inhibited RB phosphorylation at the CDK4/6-specific sites Ser780 and Ser807/811 in a dose-dependent manner and dramatically inhibited liposarcoma cell growth. Cell cycle analysis demonstrated arrest at G0/G1. siRNA-mediated knockdown of RB1 rescued the inhibitory effects of LEE011, suggesting that LEE011 inhibited proliferation as expected through the RB pathway. Oral administration of LEE011 to mice bearing human liposarcoma xenografts reduced tumor 18F-FDG uptakes by approximately 50% and dramatically decreased biomarkers including RB phosphorylation and BrdU incorporation in vivo. Continued LEE011 treatment inhibited growth of established cell line xenografts as well as primary human liposarcoma tumor xenografts without detrimental effects on mouse weight. Conclusions: LEE011 decreases cell cycle progression, hypermetabolism, and proliferation of human liposarcomas in an RB-dependent manner, consistent with inhibition of CDK4. Clinical trials of LEE011 in patients with liposarcoma are warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A236.