TY - JOUR
T1 - A screening-based approach identifies cell cycle regulators AURKA, CHK1 and PLK1 as targetable regulators of chondrosarcoma cell survival
AU - de Jong, Yvonne
AU - Bennani, Fairuz
AU - van Oosterwijk, Jolieke G.
AU - Alberti, Gaia
AU - Baranski, Zuzanna
AU - Wijers-Koster, Pauline
AU - Venneker, Sanne
AU - Briaire-de Bruij, Inge H.
AU - van de Akker, Brendy E.
AU - Baelde, Hans
AU - Cleton-Jansen, Anne Marie
AU - van de Water, Bob
AU - Danen, Erik H.J.
AU - Bovée, Judith V.M.G.
N1 - Funding Information:
This work was financially supported by Dutch Cancer Society (UL2010-4873 and UL2013-6103) and performed in the context of EuroSARC, a collaborative project within the EC's 7th Framework programme under grant agreement 278742. We are grateful to Dr JA Block (Rush University Medical Centre, Chicago, IL, USA), who provided us with the JJ012 cell line and Professor A Llombart Bosch (University of Valencia, Spain) for the CH2879 and CH3573 cell lines. Also we would like to thank M Namba (Okayama University Medical School, Shikata, Japan) for the OUMS27 cell line, Professor J.A. Fletcher for the MCS-170 cell line and Dr T Ariizumi (Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan) for the cell line NDCS-1.
Funding Information:
This work was financially supported by Dutch Cancer Society ( UL2010-4873 and UL2013-6103 ) and performed in the context of EuroSARC , a collaborative project within the EC's 7th Framework programme under grant agreement 278742 .
Publisher Copyright:
© 2019 The Authors
PY - 2019/12
Y1 - 2019/12
N2 - 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 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.
AB - 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 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.
KW - AURKA
KW - CHK1
KW - Chondrosarcoma
KW - PLK1
KW - Screen
UR - http://www.scopus.com/inward/record.url?scp=85075427166&partnerID=8YFLogxK
U2 - 10.1016/j.jbo.2019.100268
DO - 10.1016/j.jbo.2019.100268
M3 - Article
SN - 2212-1374
VL - 19
JO - Journal of Bone Oncology
JF - Journal of Bone Oncology
M1 - 100268
ER -