title: Preclinical Characterization of Novel Chordoma Cell Systems and Their Targeting by Pharmocological Inhibitors of the CDK4/6 Cell-Cycle Pathway.
abstract: 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.
authors.affiliation: Institute of Pathology, University of Ulm, Ulm, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: von Witzleben
authors.affiliation: Institute of Pathology, University of Ulm, Ulm, Germany.
authors.forename: Lukas T
authors.initials: LT
authors.lastname: Goerttler
authors.affiliation: Institute of Pathology, University of Ulm, Ulm, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Marienfeld
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm, Ulm, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Barth
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.affiliation: Institute of Pathology, University of Ulm, Ulm, Germany.
authors.forename: Kevin
authors.initials: K
authors.lastname: Mellert
authors.affiliation: Institute of Pathology, University of Ulm, Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.affiliation: Department of General and Visceral Surgery, University of Ulm, Ulm, Germany.
authors.forename: Marko
authors.initials: M
authors.lastname: Kornmann
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: Regine
authors.initials: R
authors.lastname: Mayer-Steinacker
authors.affiliation: Department of Trauma Surgery, University of Ulm, Ulm, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: von Baer
authors.affiliation: Department of Trauma Surgery, University of Ulm, Ulm, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schultheiss
authors.affiliation: Cancer Institute, University College London (UCL), London, United Kingdom.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
authors.affiliation: Institute of Pathology, University of Ulm, Ulm, Germany. peter.moeller@uniklinik-ulm.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.affiliation: Institute of Pathology, University of Ulm, Ulm, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Brüderlein
authors.affiliation: Institute of Pathology, University of Ulm, Ulm, Germany.
authors.forename: Thomas F E
authors.initials: TF
authors.lastname: Barth
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000201:enzymology; D002817:Chordoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D012447:Sacrum; D013125:Spinal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D001562:Benzimidazoles; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C000590451:abemaciclib; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib