title: Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo.
abstract: Well-differentiated/dedifferentiated liposarcomas (WD/DDLPS) are among the most common subtypes of soft tissue sarcomas. Conventional systemic chemotherapy has limited efficacy and novel therapeutic strategies are needed to achieve better outcomes for patients. The cyclin-dependent kinase 4 (CDK4) gene is highly amplified in more than 95% of WD/DDLPS. In this study, we explored the role of CDK4 and the effects of NVP-LEE011 (LEE011), a novel selective inhibitor of CDK4/CDK6, on a panel of human liposarcoma cell lines and primary tumor xenografts. We found that both CDK4 knockdown by siRNA and inhibition by LEE011 diminished retinoblastoma (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 (18)F-fluorodeoxyglucose uptake with 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. These findings validate the critical role of CDK4 in maintaining liposarcoma proliferation through its ability to inactivate RB function, and suggest its potential function in the regulation of survival and metabolism of liposarcoma, supporting the rationale for clinical development of LEE011 for the treatment of WD/DDLPS.
authors.affiliation: Ludwig Center at Dana-Farber/Harvard, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Yi-Xiang
authors.initials: YX
authors.lastname: Zhang
authors.affiliation: Ludwig Center at Dana-Farber/Harvard, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Ewa
authors.initials: E
authors.lastname: Sicinska
authors.affiliation: Ludwig Center at Dana-Farber/Harvard, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Czaplinski
authors.affiliation: Ludwig Center at Dana-Farber/Harvard, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Remillard
authors.affiliation: Ludwig Center at Dana-Farber/Harvard, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Samuel
authors.initials: S
authors.lastname: Moss
authors.affiliation: Department of Radiology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Christopher
authors.initials: C
authors.lastname: Brain
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Alice
authors.initials: A
authors.lastname: Loo
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Snyder
authors.affiliation: Ludwig Center at Dana-Farber/Harvard, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Ludwig Center at Dana-Farber/Harvard, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Andrew_Wagner@dfci.harvard.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight; D002453:Cell Cycle; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D008080:Liposarcoma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6