Cancer research (Chicago, Ill.), 2015-09, Vol.75 (18), p.3823-3831
2015
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Details
- Autor(en) / Beteiligte
- Titel
- Preclinical Characterization of Novel Chordoma Cell Systems and Their Targeting by Pharmocological Inhibitors of the CDK4/6 Cell-Cycle Pathway
- Ist Teil von
- Cancer research (Chicago, Ill.), 2015-09, Vol.75 (18), p.3823-3831
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Chordomas are tumors that arise at vertebral bodies and the base of the skull. Although rare in incidence, they are deadly owing to slow growth and a lack of effective therapeutic options. In this study, we addressed the need for chordoma cell systems that can be used to identify therapeutic targets and empower testing of candidate pharmacologic drugs. Eight human chordoma cell lines that we established exhibited cytology, genomics, mRNA, and protein profiles that were characteristic of primary chordomas. Candidate responder profiles were identified through an immunohistochemical analysis of a chordoma tissue bank of 43 patients. Genomic, mRNA, and protein expression analyses confirmed that the new cell systems were highly representative of chordoma tissues. Notably, all cells exhibited a loss of CDKN2A and p16, resulting in universal activation of the CDK4/6 and Rb pathways. Therefore, we investigated the CDK4/6 pathway and responses to the CDK4/6-specific inhibitor palbociclib. In the newly validated system, palbociclib treatment efficiently inhibited tumor cell growth in vitro and a drug responder versus nonresponder molecular signature was defined on the basis of immunohistochemical expression of CDK4/6/pRb (S780). Overall, our work offers a valuable new tool for chordoma studies including the development of novel biomarkers and molecular targeting strategies.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.CAN-14-3270Titel-ID: cdi_proquest_miscellaneous_1811906758
- Format
- –
- Schlagworte
- Adolescent, Adult, Aged, Aged, 80 and over, Aminopyridines - pharmacology, Benzimidazoles - pharmacology, Cell Cycle - drug effects, Cell Line, Tumor - drug effects, Cell Line, Tumor - enzymology, Chordoma - enzymology, Chordoma - genetics, Chordoma - pathology, Cyclin-Dependent Kinase 4 - antagonists & inhibitors, Cyclin-Dependent Kinase 6 - antagonists & inhibitors, Drug Screening Assays, Antitumor, Female, Gene Deletion, Gene Expression Regulation, Neoplastic, Genes, p16, Humans, Male, Middle Aged, Molecular Targeted Therapy, Neoplasm Proteins - antagonists & inhibitors, Piperazines - pharmacology, Protein Kinase Inhibitors - pharmacology, Pyridines - pharmacology, RNA, Messenger - biosynthesis, RNA, Messenger - genetics, RNA, Neoplasm - biosynthesis, RNA, Neoplasm - genetics, Sacrum, Spinal Neoplasms - enzymology, Spinal Neoplasms - genetics, Spinal Neoplasms - pathology, Young Adult