Documents
In Collections
This item can be found in the following collections:
A screening-based approach identifies cell cycle regulators AURKA, CHK1 and PLK1 as targetable regulators of chondrosarcoma cell survival
Chondrosarcomas are malignant cartilage tumors that are relatively resistant towards conventional therapeutic
approaches. Kinase inhibitors have been investigated and shown successful for several different cancer types. In
this study we aimed at identifying kinase inhibitors that inhibit the survival of chondrosarcoma cells and thereby
serve as new potential therapeutic strategies to treat chondrosarcoma patients.
An siRNA screen targeting 779 different kinases was conducted in JJ012 chondrosarcoma cells in parallel
with a compound screen consisting of 273 kinase inhibitors in JJ012, SW1353 and CH2879 chondrosarcoma cell
lines. AURKA, CHK1 and PLK1 were identified as most promising targets and validated further in a more
comprehensive panel of chondrosarcoma cell lines. Dose response curves were performed using tyrosine kinase
inhibitors: MK-5108 (AURKA), LY2603618 (CHK1) and Volasertib (PLK1) using viability assays and cell cycle<...
Show moreChondrosarcomas are malignant cartilage tumors that are relatively resistant towards conventional therapeutic
approaches. Kinase inhibitors have been investigated and shown successful for several different cancer types. In
this study we aimed at identifying kinase inhibitors that inhibit the survival of chondrosarcoma cells and thereby
serve as new potential therapeutic strategies to treat chondrosarcoma patients.
An siRNA screen targeting 779 different kinases was conducted in JJ012 chondrosarcoma cells in parallel
with a compound screen consisting of 273 kinase inhibitors in JJ012, SW1353 and CH2879 chondrosarcoma cell
lines. AURKA, CHK1 and PLK1 were identified as most promising targets and validated further in a more
comprehensive panel of chondrosarcoma cell lines. Dose response curves were performed using tyrosine kinase
inhibitors: MK-5108 (AURKA), LY2603618 (CHK1) and Volasertib (PLK1) using viability assays and cell cycle
analysis. Apoptosis was measured at 24 h after treatment using a caspase 3/7 assay. Finally, chondrosarcoma
patient samples (N = =34) were used to examine the correlation between AURKA, CHK1 and PLK1 RNA
expression and documented patient survival.
Dose dependent decreases in viability were observed in chondrosarcoma cell lines after treatment with MK-
5108, LY2603618 and volasertib, with cell lines showing highest sensitivity to PLK1 inhibition. In addition
increased sensitivity to conventional chemotherapy was observed after CHK1 inhibition in a subset of the cell
lines. Interestingly, whereas AURKA and CHK1 were both expressed in chondrosarcoma patient samples, PLK1
expression was found to be low compared to normal cartilage. Analysis of patient samples revealed that high
CHK1 RNA expression correlated with a worse overall survival.
AURKA, CHK1 and PLK1 are identified as important survival genes in chondrosarcoma cell lines. Although
further research is needed to validate these findings, inhibiting CHK1 seems to be the most promising potential
therapeutic target for patients with chondrosarcoma.
Show less- All authors
- Jong, Y. de; Bennani, F.; Oosterwijk, J.G. van; Alberti, G.; Baranski, Z.; Wijers-Koster, P.; Venneker, S.; Briaire-de Bruij, I.H.; Akker, B.E. van de; Baelde, H.; Cleton-Jansen, A.M.; Water, B. van de; Danen, E.H.J.; Bovée, J.V.M.G.
- Date
- 2019-12-31
- Journal
- Journal of Bone Oncology
- Volume
- 19
- Pages
- 100268