Analysis of the CDK4/6 Cell Cycle Pathway in Leiomyosarcomas as a Potential Target for Inhibition by Palbociclib.
Leiomyosarcoma (LMS) is characterized by high genomic complexity, and to date, no specific targeted therapy is available. In a genome-wide approach, we profiled genomic aberrations in a small cohort of eight primary tumours, two relapses, and eight metastases across nine different patients. We ident...
| Publicado en: | Sarcoma pp. 1 - 11 |
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| Autores principales: | , , , , , , , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
Wiley-Blackwell
1/21/2019
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=134209329&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 134209329 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 1357714X 57R jtl: Sarcoma issn: 1357714X maglogo: Y pubinfo: dt: 1/21/2019 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 134209329 134209329 134209329 10.1155/2019/3914232 134209329 ppf: 1 ppct: 10 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Analysis of the CDK4/6 Cell Cycle Pathway in Leiomyosarcomas as a Potential Target for Inhibition by Palbociclib. aug: au: Böhm, Michael J. Marienfeld, Ralf Jäger, Daniela Mellert, Kevin von Witzleben, Adrian Brüderlein, Silke Wittau, Mathias von Baer, Alexandra Schultheiss, Markus Mayer-Steinacker, Regine Rücker, Frank G. Möller, Peter Bullinger, Lars Barth, Thomas F. E. affil: Institute of Pathology, Ulm University, Ulm, Germany sug: subj: Leiomyosarcoma Drug Therapy Protein Kinase Inhibitors Pharmacodynamics Cell Cycle Drug Effects Transferases Drug Effects Cell Line, Tumor Drug Effects Drug Delivery Systems Genomics Human In Vitro Studies Neoplasm Metastasis Neoplasm Recurrence, Local Gene Expression Drug Effects Cell Proliferation Drug Effects Immunohistochemistry Phenotype ab: Leiomyosarcoma (LMS) is characterized by high genomic complexity, and to date, no specific targeted therapy is available. In a genome-wide approach, we profiled genomic aberrations in a small cohort of eight primary tumours, two relapses, and eight metastases across nine different patients. We identified CDK4 amplification as a recurrent alteration in 5 out of 18 samples (27.8%). It has been previously shown that the LMS cell line SK-LMS-1 has a defect in the p16 pathway and that this cell line can be inhibited by the CDK4 and CDK6 inhibitor palbociclib. For SK-LMS-1 we confirm and for SK-UT-1 we show that both LMS cell lines express CDK4 and that, in addition, strong CDK6 expression is seen in SK-LMS-1, whereas Rb was expressed in SK-LMS-1 but not in SK-UT-1. We confirm that inhibition of SK-LMS-1 with palbociclib led to a strong decrease in protein levels of Phospho-Rb (Ser780), a decreased cell proliferation, and G0/G1-phase arrest with decreased S/G2 fractions. SK-UT-1 did not respond to palbociclib inhibition. To compare these in vitro findings with patient tissue samples, a p16, CDK4, CDK6, and p-Rb immunohistochemical staining assay of a large LMS cohort (n=99 patients with 159 samples) was performed assigning a potential responder phenotype to each patient, which we identified in 29 out of 99 (29.3%) patients. Taken together, these data show that CDK4/6 inhibitors may offer a new option for targeted therapy in a subset of LMS patients. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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