Characterization of chordoma cell lines and inhibition of the CDK4/6 pathway

Introduction:

Chordomas are rare, malignant primary tumors of the bone, which are supposed to arise from the rests of the chorda dorsalis along the spine. Clival chordoma are interfere with ENT and are operated in an interdisciplinary approach. Due to the generally slow proliferation rate of chordomas, these tumors have low response rates to conventional chemotherapy. Therefore new therapeutical options based on targeted therapy are needed.

Material and Methods:

We established a chordoma collective with 43 patients and characterize 6 stable chordoma cell lines. The cell lines were characterized by means of mRNA-microssay and western blot analysis. The collective was defined through immunohistochemical staining. After that we performed an inhibition test with a CDK4/6 inhibitor palbociclib. The growth inhibition was detected by western blot, cell cycle analysis and MTS cell viability assays.

Results:

The chordomas of the collective and the cell lines showed a recurrent loss of CDKN2 and a loss of p16 protein expression over 90%. This leads to a constitutively active p16 cascade, loss of control of the cyclin depended kinases CDK4/6 and an active cell cycle. We are able to show that palbociclib as a specific CDK4/6 inhibitor significantly inhibits growth in several chordoma cell lines in vitro. Over 85% of the patients in the collective present a potential immunohistochemical „responder phenotype” for a possible therapy with palbociclib.

Conclusion:

Due to this data a clinical trial under the guidance of the NCT in Heidelberg (Prof. Schlenk/Prof. Fröhlich) will be launched this year (NCT03110744) in Germany.

Publikationsverlauf

Publikationsdatum:
18. April 2018 (online)