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Analysis of the CDK4/6 Cell Cycle Pathway in Leiomyosarcomas as a Potential Target for Inhibition by Palbociclib

Authors :
Thomas F. E. Barth
Regine Mayer-Steinacker
Silke Brüderlein
Markus Schultheiss
Kevin Mellert
Lars Bullinger
Alexandra von Baer
Peter Möller
Michael J. Böhm
Daniela Jager
Adrian von Witzleben
Frank G. Rücker
Ralf Marienfeld
Mathias Wittau
Source :
Sarcoma, Vol 2019 (2019), Sarcoma
Publication Year :
2019
Publisher :
Hindawi Limited, 2019.

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 G0/G1-phase arrest with decreased S/G2fractions. SK-UT-1 did not respond to palbociclib inhibition. To compare thesein vitrofindings with patient tissue samples, a p16, CDK4, CDK6, and p-Rb immunohistochemical staining assay of a large LMS cohort (n=99patients 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.

Details

ISSN :
13691643 and 1357714X
Volume :
2019
Database :
OpenAIRE
Journal :
Sarcoma
Accession number :
edsair.doi.dedup.....a488de0fe2c40d65ad14d98f9c0869b6
Full Text :
https://doi.org/10.1155/2019/3914232