Analysis of the CDK4/6 cell cycle pathway in leiomyosarcomas as a potential target for inhibition by palbociclib

Böhm, M.J.; Marienfeld, R.; Jäger, D.; Mellert, K.; von Witzleben, A.; Brüderlein, S.; Wittau, M.; von Baer, A.; Schultheiss, M.; Mayer-Steinacker, R.; Rücker, F.G.; Möller, P.; Bullinger, L.; Barth, T.F.E.

Analysis of the CDK4/6 cell cycle pathway in leiomyosarcomas as a potential target for inhibition by palbociclib

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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., Marienfeld, R., Jäger, D., Mellert, K., von Witzleben, A., Brüderlein, S., Wittau, M., von Baer, A., Schultheiss, M., Mayer-Steinacker, R., Rücker, F.G., Möller, P., 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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