Kinome profiling of chondrosarcoma reveals SRC-pathway activity and dasatinib as option for treatment.
Chondrosarcomas are notorious for their resistance to conventional chemotherapy and radiotherapy, indicating there are no curative treatment possibilities for patients with inoperable or metastatic disease. We therefore explored the existence of molecular targets for systemic treatment of chondrosarcoma using kinome profiling. Peptide array was performed for four chondrosarcoma cell lines and nine primary chondrosarcoma cultures with GIST882, MSCs, and colorectal cancer cell lines as controls. Activity of kinases was verified using immunoblot, and active Src- and platelet-derived growth factor receptor (PDGFR) signaling were further explored using imatinib and dasatinib on chondrosarcoma in vitro. The AKT1/GSK3B pathway was clearly active in chondrosarcoma. In addition, the PDGFR pathway and the Src kinase family were active. PDGFR and Src kinases can be inhibited by imatinib and dasatinib, respectively. Although imatinib did not show any effect on chondrosarcoma cell cultures, dasatinib showed a decrease in cell viability at nanomolar concentrations in seven of nine chondrosarcoma cultures. However, inhibition of phosphorylated Src (Y419) was found both in responsive and nonresponsive cells. In conclusion, using kinome profiling, we found the Src pathway to be active in chondrosarcoma. Moreover, we showed in vitro that the inhibitor of the Src pathway, dasatinib, may provide a potential therapeutic benefit for chondrosarcoma patients who are not eligible for surgery.
Schrage
Yvonne M
YM
Department of Pathology and Orthopedic Surgery, Leiden University Medical Center, Leiden, the Netherlands.
Briaire-de Bruijn
Inge H
IH
de Miranda
Noel F C C
NF
van Oosterwijk
Jolieke
J
Taminiau
Antonie H M
AH
van Wezel
Tom
T
Hogendoorn
Pancras C W
PC
Bovée
Judith V M G
JV
D001549:Benzamides; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000188:drug therapy / Q000201:enzymology*; D000069439:Dasatinib; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D000068877:Imatinib Mesylate; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D019061:src-Family Kinases; C494918:AKT1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D038362:Glycogen Synthase Kinase 3; D018631:ras Proteins; D000069439:Dasatinib