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| Item Type: | Article |
|---|---|
| Title: | Analysis of the CDK4/6 cell cycle pathway in leiomyosarcomas as a potential target for inhibition by palbociclib |
| Creators Name: | Böhm, M.J. and Marienfeld, R. and Jäger, D. and Mellert, K. and von Witzleben, A. and Brüderlein, S. and Wittau, M. and von Baer, A. and Schultheiss, M. and Mayer-Steinacker, R. and Rücker, F.G. and Möller, P. and Bullinger, L. and Barth, T.F.E. |
| Abstract: | 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 G/G-phase arrest with decreased S/G fractions. SK-UT-1 did not respond to palbociclib inhibition. To compare these findings with patient tissue samples, a p16, CDK4, CDK6, and p-Rb immunohistochemical staining assay of a large LMS cohort (=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. |
| Source: | Sarcoma |
| ISSN: | 1357-714X |
| Publisher: | Hindawi |
| Volume: | 2019 |
| Page Range: | 3914232 |
| Date: | 21 January 2019 |
| Official Publication: | https://doi.org/10.1155/2019/3914232 |
| PubMed: | View item in PubMed |
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